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Progress of NRF2 Signaling Pathway in Promoting Proliferation of Non-small Cell Lung Cancer.

The morbidity and mortality of lung cancer ranks among the top cancers in the world. Non-small cell lung cancer (NSCLC) is the main pathological type of lung cancer, with limited treatment options and poor prognosis. The nuclear factor E2-related factor 2 (NRF2) signaling pathway is highly mutated and activated in NSCLC, and promotes the malignant progression of lung cancer through various mechanisms. NRF2-targeted therapy will provide new treatment strategies for patients with NSCLC. This article will review the basic structure and response pathways of the NRF2 pathway, the mechanism of NRF2 regulating lung cancer cell proliferation, and the research and development progress of NRF2 inhibitors. . 【中文题目：NRF2信号通路促进非小细胞肺癌增殖 的研究进展】 【中文摘要：肺癌的发病率和死亡率位居全球癌症前列，非小细胞肺癌（non-small cell lung cancer, NSCLC）是肺癌的主要病理类型，且治疗手段有限，患者预后较差。细胞核因子E2相关因子2（nuclear factor E2-related factor, NRF2）信号通路在NSCLC中高度突变激活，并通过多种机制促进肺癌的恶性进展，以NRF2为靶点的治疗方案将为NSCLC患者提供新的治疗策略。本文将对NRF2通路的基本结构和反应途径、NRF2调节肺癌细胞增殖的机制，及NRF2抑制剂的研发进展进行综述。 】 【中文关键词：肺肿瘤；增殖；NRF2】.

Comparison of Two-dimensional and Three-dimensional Features of Chest CT in the Diagnosis of Invasion of Pulmonary Ground Glass Nodules.

At present, more and more studies predict invasive adenocarcinoma (IAC) through three-dimensional features of pulmonary nodules, but few studies have confirmed that three-dimensional features have more advantages in diagnosing IAC than traditional two-dimensional features of pulmonary nodules. This study analyzed the differences of chest computed tomography (CT) features between IAC and minimally invasive adenocarcinoma (MIA) from three-dimensional and two-dimensional levels, and compared the ability of diagnosing IAC. The non-invasive adenocarcinoma group includes precursor glandular lesions (PGL) and minimally invasive adenocarcinoma (MIA). The clinical data of 1,045 patients with ground glass opacity (GGO) from January to December 2019 were collected. Then the correlation between preoperative CT image characteristics and pathological results were analyzed retrospectively. The independent influencing factors for the identification of IAC were screened out according to two-dimensional and three-dimensional classification by multivariate Logistic regression and the cut-off point for the identification of IAC was found out through the receiver operating characteristic (ROC) curve. At last, the ability of diagnosing IAC was evaluated by Yoden index. The diameter of nodule, the diameter of solid component, the diameter of mediastinal window nodule in two-dimensional factors, and the volume of nodule, the volume of solid part and the average CT value in three-dimensional factors were independent risk factors for the diagnosis of IAC. These factors were arranged by Yoden index solid partial volume (0.601)>nodule volume (0.536)>solid component diameter (0.525)>nodule diameter (0.518)>mediastinal window nodule diameter (0.488)>proportion of solid component volume (0.471)>1-tumor disappearance ratio (TDR) (0.468)>consolidation tumor ratio (CTR) (0.394)>average CT value (0.380). The CT features of three-dimensional are better than two-dimensional in the diagnosis of IAC, and the size of solid components is better than the overall size of nodules. 【中文题目：胸部CT二维与三维特征对肺磨玻璃结节 浸润性的诊断效能对比】 【中文摘要：背景与目的 目前越来越多的研究通过肺结节三维特征预测浸润性腺癌（invasive adenocarcinoma, IAC），但少有研究证实与传统的肺结节二维特征相比，三维特征诊断IAC更有优势。本文分别从三维与二维层面分析IAC与非浸润性腺癌组胸部计算机断层扫描（computed tomography, CT）特征差异，比较二者鉴别IAC的优劣，其中非浸润性腺癌组包括前驱性腺体病变（precursor glandular lesions, PGL）及微浸润性腺癌（minimally invasive adenocarcinoma, MIA）。方法 收集2019年1月-2019年12月1,045例肺磨玻璃结节（ground-glass opacity, GGO）手术患者临床资料，回顾性分析术前CT影像特征与病理学结果的相关性，由多因素Logistic回归分别按二维与三维分类筛选出鉴别IAC的独立影响因素，通过受试者工作特征（receiver operating characteristic, ROC）曲线找出鉴别IAC的cut-off值，并以约登指数评估诊断IAC的能力。结果 二维因素中结节最大径、实性成分最大径、纵隔窗结节最大径以及三维因素中结节总体积、实性部分体积、平均CT值均是诊断IAC的独立危险因素。将各项指标通过约登指数排列：实性部分体积（0.601）>结节体积（0.536）>实性成分最大径（0.525）>结节最大径（0.518）>纵隔窗结节最大径（0.488）>实性成分体积占比（0.471）> 肿瘤消失率（tumor disappearance ratio, TDR）（0.468）>实性成分占比（consolidationtumor ratio, CTR）（0.394）>平均CT值（0.380）。结论 三维层面CT特征诊断IAC优于二维层面，实性成分大小优于结节总体大小。 】 【中文关键词：肺肿瘤；放射学；计算机断层扫描；计算机三维成像；体积】.

Therapeutic Response of Multifunctional Lipid and Micelle Formulation in Hepatocellular Carcinoma.

Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the CAFs-ECM axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pH-sensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCsBEL-7402 cocultured cell model and a m-HSCsH22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLsDGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipidmicelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the CAFs-ECM axis, which has a good clinical application prospect.

The association between cancer diagnosis, care, and outcomes in 1 million patients hospitalized for acute pulmonary embolism.

To evaluate the clinical care provided to cancer patients hospitalized for acute pulmonary embolism (PE), as well as the association between type of cancer, in-hospital care, and clinical outcomes. This study examined the in-hospital care (systemic thrombolysis, catheter-directed thrombolysis, and surgical thrombectomyembolectomy) and clinical outcomes (mortality, major bleeding, and hemorrhagic stroke) among adults hospitalized due to acute PE between October 2015 to December 2018 using the National Inpatient Sample (NIS). Multivariable logistic regression analysis was used to determine adjusted odds ratios (aOR) with 95% confidence interval (95% CI). Of 1,090,130 hospital records included in the analysis, 216,825 (19.9%) had current cancer diagnoses, including lung (4.7%), hematological (2.5%), colorectal (1.6%), breast (1.3%), prostate (0.8%), and other cancer (9.0%). Cancer patients had lower adjusted odds of receiving systemic thrombolysis, catheter-directed therapy, and surgical thrombectomyembolectomy compared with their non-cancer counterparts (P < 0.001), except for systemic thrombolysis (aOR 0.96, 95% CI 0.85-1.09, P 0.553) and catheter-directed therapy (aOR 0.82, 95% CI 0.67-1.00, P 0.053) for prostate cancer. Cancer patients had greater odds of mortality (P < 0.05). Lung cancer patients had the highest odds of mortality (aOR 2.68, 95% CI 2.61-2.76, P < 0.001) and hemorrhagic stroke (aOR 1.75, 95% CI 1.61-1.90, P < 0.001), while colorectal cancer patients had the greatest odds of bleeding (aOR 2.04, 95% CI 1.94-2.15, P < 0.001). Among those hospitalized for PE, cancer diagnoses were associated with lower odds of invasive management and poorer in-hospital outcomes, with metastatic status being an especially important determinant. Appropriateness of care could not be assessed in this study.

Automated clinical decision support system with deep learning dose prediction and NTCP models to evaluate treatment complications in patients with esophageal cancer.

This study aims to investigate how accurate our deep learning (DL) dose prediction models for intensity modulated radiotherapy (IMRT) and pencil beam scanning (PBS) treatments, when chained with normal tissue complication probability (NTCP) models, are at identifying esophageal cancer patients who are at high risk of toxicity and should be switched to proton therapy (PT). Two U-Net were created, for photon (XT) and proton (PT) plans, respectively. To estimate the dose distribution for each patient, they were trained on a database of 40 uniformly planned patients using cross validation and a circulating test set. These models were combined with a NTCP model for postoperative pulmonary complications. The NTCP model used the mean lung dose, age, histology type, and body mass index as predicting variables. The treatment choice is then done by using a ΔNTCP threshold between XT and PT plans. Patients with ΔNTCP ≥ 10% were referred to PT. Our DL models succeed in predicting dose distributions with a mean error on the mean dose to the lungs (MLD) of 1.14 ± 0.93% for XT and 0.66 ± 0.48% for PT. The complete automated workflow (DL chained with NTCP) achieved 100% accuracy in patient referral. The average residual (ΔNTCP ground truth - ΔNTCP predicted) is 1.43 ± 1.49%. This study evaluates our DL dose prediction models in a broader patient referral context and demonstrates their ability to support clinical decisions.

Automated discovery of nanomaterials via drug aggregation induced emission.

Nanoformulations of small molecule drugs are essential to effectively deliver them and treat a wide range of diseases. They are normally complex to develop, lack predictability, and exhibit low drug loading. Recently, nanoparticles made via co-assembly of hydrophobic drugs and organic dyes, exhibited drug-loading of up to 90% with high predictability from the drug structure. However, these particles have relatively short stability and can formulate only a small fraction of the drug space. Here, we developed an automated workflow to synthesize and select novel dye stabilizers, based on their ability to inhibit drug aggregation-induced emission (AIE). We first screened and identified 10 drugs with previously unknown strong AIE activity and exploited this trait to automatically synthesize and select a new ultra-stabilizer named R595. Interestingly, it shares several synthetic similarities and advantages with polydopamine. We found that R595 is superior to myriad types of excipients and solubilizers such as cyclodextrins, poloxamers, albumin, and previously published organic dyes, in both long-term stability and drug compatibility. We investigated the biodistribution, pharmacokinetics, safety and efficacy of the AIEgenic MEK inhibitor trametinib-R595 nanoparticles in vitro and in vivo and demonstrated that they are non-toxic and effective in KRAS driven colon and lung cancer models.

Long-term survival after immunotherapy and targeted therapy without chemotherapy in an elderly patient with HER2-positive gastroesophageal junction cancer A case report.

A 74-yr-old man underwent thoracic laparoscopy combined with radical gastrectomy, and the postoperative pathological diagnosis was esophageal and gastric cardia cancer pT3N1M0, pStage IIB. Immunohistochemical staining for HER2 (3) and PD-L1 (<5%) was positive. Adjuvant chemotherapy was not performed because the patient developed severe thrombocytopenia (platelet counts <30 × 10

ALERT-RA an aperture library-enabled real-time respiratory motion adaptive framework for 4D-VMAT.

To develop a framework for robust optimization of real-time respiratory motion adaptive VMAT treatment plans, and to evaluate the robustness of resulting plans to variations in tumor trajectory during delivery. The proposed framework is called aperture library-enabled real-time robust adaptation (ALERT-RA). A patient-specific library of optimized MLC apertures is defined for each combination of gantry angle and respiratory phase. The method assumes that the tumor is tracked in real-time throughout delivery, and the aperture corresponding to the current phase and gantry angle will be delivered. The aperture library is optimized by considering all possible tumor trajectories determined by a probabilistic respiratory motion model. Plan robustness to trajectory variations was evaluated by sampling a trajectory, and determining the corresponding dose, from the respiratory model for each fraction. The cumulative dose of the full treatment course was simulated 50 times. Percentile dose-volume histograms (PDVHs) were computed from these simulated treatments. The resulting plan quality and robustness of this method were compared to other previously published motion 4D-VMAT methods, including an optimized tracking approach that assumes reproducible tumor motion, conformal tracking with aperture deformation, and a motion-encompassing method. Two fractionation schemes were tested to determine the possible effect on robustness a conventional fractionation of 66 Gy in 33 fractions, and an SBRT course with 60 Gy in 5 fractions. When considering target coverage, the ALERT-RA method was found to produce a plan which was more robust than those produced using the optimized or conformal tracking methods. Using the PDVH analysis, the 5th and 95th percentiles of the prescription dose volume for the conventionally fractioned plan were found to be (respectively) 79% and 82% for the optimized tracking approach, 81% and 83% for the conformal tracking approach, and 92% and 97% using the new ALERT-RA method. The motion-encompassing plan was slightly more robust than the ALERT-RA plan, with 5th and 95th percentiles at 94% and 95%, respectively. This came at a cost of higher dose to OARs, with the volume of lung receiving 5 Gy or more equal to 48% for the motion-encompassing plan versus 44% for the ALERT-RA plan. For the SBRT plan, the conformal tracking plan was similarly not robust, with 5th and 95th percentiles of the prescription dose volume equal to 88% and 89%. The optimized tracking SBRT plan gave values of 93% and 95%, and the motion-encompassing plan 94% and 95%, while the ALERT-RA gave values of 93% and 96%. The volume of lung receiving 20 Gy or more was slightly higher for the optimized tracking and motion-encompassing plans compared to the ALERT-RA plan, at 15%, 15%, and 14%, respectively. Compared to other motion-adaptive VMAT approaches, the ALERT-RA algorithm is capable of delivering high-quality plans which are robust to variations in tumor motion trajectories.

Screening for differentially expressed microRNAs in BALF and blood samples of infected COVID-19 ARDS patients by small RNA deep sequencing.

The pandemic COVID-19 has caused a high mortality rate and poses a significant threat to the population of the entire world. Due to the novelty of this disease, the pathogenic mechanism of the disease and the host cells response are not yet fully known, so lack of evidence prevents a definitive conclusion about treatment strategies. The current study employed a small RNA deep-sequencing approach for screening differentially expressed microRNA (miRNA) in blood and bronchoalveolar fluid (BALF) samples of acute respiratory distress syndrome (ARDS) patients. In this study, BALF and blood samples were taken from patients with ARDS (n 5). Control samples were those with suspected lung cancer candidates for lung biopsy (n 3). Illumina high-throughput (HiSeq 2000) sequencing was performed to identify known and novel miRNAs differentially expressed in the blood and BALFs of ARDS patients compared with controls. Results showed 2234 and 8324 miRNAs were differentially expressed in blood and BALF samples, respectively. In BALF samples, miR-282, miR-15-5p, miR-4485-3p, miR-483-3p, miR-6891-5p, miR-200c, miR-4463, miR-483-5p, and miR-98-5p were upregulated and miR-15a-5p, miR-548c-5p, miR-548d-3p, miR-365a-3p, miR-3939, miR-514-b-5p, miR-513a-3p, miR-513a-5p, miR-664a-3p, and miR-766-3p were downregulated. On the contrary, in blood samples miR-15b-5p, miR-18a-3p, miR-486-3p, miR-486-5p, miR-146a-5p, miR-16-2-3p, miR-6501-5p, miR-365-3p, miR-618, and miR-623 were top upregulated miRNAs and miR-21-5p, miR-142a-3p, miR-181-a, miR-31-5p, miR-99-5p, miR-342-5p, miR-183-5p, miR-627-5p, and miR-144-3p were downregulated miRNAs. Network functional analysis for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), in ARDS patients blood and BALF samples, showed that the target genes were more involved in activating inflammatory and apoptosis process. Based on our results, the transcriptome profile of ARDS patients would be a valuable source for understanding molecular mechanisms of host response and developing clinical guidance on anti-inflammatory medication.

Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation.

Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function, which leads to a fatal outcome. As an essential epigenetic regulator of DNA methylation, the involvement of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in fibroblast activation remains largely undefined in pulmonary fibrosis. In the present study, we found that TGF-β1-mediated upregulation of UHRF1 repressed beclin 1 via methylated induction of its promoter, which finally resulted in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated beclin 1 in lung fibroblasts. Thus, intravenous administration of UHRF1 siRNA-loaded liposomes significantly protected mice against experimental pulmonary fibrosis. Accordingly, our data suggest that UHRF1 might be a novel potential therapeutic target in the pathogenesis of pulmonary fibrosis.

Immunogenetics associated with severe coccidioidomycosis.

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238 and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238 variants. Stimulation with a DECTIN-1 agonist induced DUOX1DUOXA1-derived hydrogen peroxide H2O2 in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Dipeptidyl Peptidase-4 Stabilizes Integrin α4β1 Complex to Promote Thyroid Cancer Cell Metastasis by Activating Transforming Growth Factor-Beta Signaling Pathway.

Prognostic analysis and risk stratification of lung adenocarcinoma undergoing EGFR-TKI therapy with time-serial CT-based radiomics signature.

To evaluate the value of time-serial CT radiomics features in predicting progression-free survival (PFS) for lung adenocarcinoma (LUAD) patients after epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy. LUAD patients treated with EGFR-TKIs were retrospectively included from three independent institutes and divided into training and validation cohorts. Intratumoral and peritumoral features were extracted from time-serial non-contrast chest CT (including pre-therapy and first follow-up images) moreover, the percentage variation per unit time (day) was introduced to adjust for the different follow-up periods of each patient. Test-retest was performed to exclude irreproducible features, while the Boruta algorithm was used to select critical radiomics features. Radiomics signatures were constructed with random forest survival models in the training cohort and compared against baseline clinical characteristics through Cox regression and nonparametric testing of concordance indices (C-indices). The training cohort included 131 patients (74 women, 56.5%) from one institute and the validation cohort encompassed 41 patients (24 women, 58.5%) from two other institutes. The optimal signature contained 10 features and 7 were unit time feature variations. The comprehensive radiomics model outperformed the pre-therapy clinical characteristics in predicting PFS (training 0.78, 95% CI 0.72, 0.84 versus 0.55, 95% CI 0.49, 0.62, p < 0.001 validation 0.72, 95% CI 0.60, 0.84 versus 0.54, 95% CI 0.42, 0.66, p < 0.001). Radiomics signature derived from time-serial CT images demonstrated optimal prognostic performance of disease progression. This dynamic imaging biomarker holds the promise of monitoring treatment response and achieving personalized management. • The intrinsic tumor heterogeneity can be highly dynamic under the therapeutic effect of EGFR-TKI treatment, and the inevitable development of drug resistance may disrupt the duration of clinical benefit. Decision-making remained challenging in practice to detect the emergence of acquired resistance during the early response phase. • Time-serial CT-based radiomics signature integrating intra- and peritumoral features offered the potential to predict progression-free survival for LUAD patients treated with EGFR-TKIs. • The dynamic imaging signature allowed for prognostic risk stratification.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer The ASTRUM-005 Randomized Clinical Trial.

Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Patients were randomized 21 to receive either 4.5 mgkg of serplulimab (n 389) or placebo (n 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Among the 585 patients who were randomized (mean age, 61.1 SD, 8.67 years 104 17.8% women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months 95% CI, 13.3 months-not evaluable) than in the placebo group (10.9 months 95% CI, 10.0-14.3 months) (hazard ratio, 0.63 95% CI, 0.49-0.82 P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months 95% CI, 5.5-6.9 months) than in the placebo group (4.3 months 95% CI, 4.2-4.5 months) (hazard ratio, 0.48 95% CI, 0.38-0.59). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. ClinicalTrials.gov Identifier NCT04063163.

Mass Cytometry Reveals Classical Monocytes, NK Cells, and ICOS CD4 T Cells Associated with Pembrolizumab Efficacy in Patients with Lung Cancer.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non-small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS CD4 T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS HR 0.25 95% confidence interval 0.12-0.51 P < 0.0001). As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Exploratory genomic analysis of high-grade neuroendocrine neoplasms across diverse primary sites.

High-grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n 46), whole exome (n 40), and gene copy number (n 43) sequencing on G3 NEN formalin-fixed, paraffin-embedded samples from diverse organs (in total, 17 were lung, 16 were gastroenteropancreatic, and 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1, and CDKN2A were significantly mutated. The CDK46 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutationsMB), with 20% having >10 mutationsMB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types focal deletion 22q13.31 (HR, 7.82 P 0.034) and arm amplification 19q (HR, 4.82 P 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.

Novel Lymphocyte-Independent Antitumor Activity by PD-1 Blocking Antibody against PD-1 Chemoresistant Lung Cancer Cells.

Antibodies against the lymphocyte PD-1 (aPD-1) receptor are cornerstone agents for advanced non-small cell lung cancer (NSCLC), based on their ability to restore the exhausted antitumor immune response. Our study reports a novel, lymphocyte-independent, therapeutic activity of aPD-1 against NSCLC, blocking the tumor-intrinsic PD-1 receptors on chemoresistant cells. PD-1 in NSCLC cells was explored in vitro at baseline, including stem-like pneumospheres, and following treatment with cisplatin both at transcriptional and protein levels. PD-1 signaling and RNA sequencing were assessed. The lymphocyte-independent antitumor activity of aPD-1 was explored in vitro, by PD-1 blockade and stimulation with soluble ligand (PD-L1s), and in vivo within NSCLC xenograft models. We showed the existence of PD-1 NSCLC cell subsets in cell lines and large in silico datasets (Cancer Cell Line Encyclopedia and The Cancer Genome Atlas). Cisplatin significantly increased PD-1 expression on chemo-surviving NSCLC cells (2.5-fold P 0.0014), while the sequential treatment with anti-PD-1 Ab impaired their recovery after chemotherapy. PD-1 was found to be associated with tumor stemness features. PD-1 expression was enhanced in NSCLC stem-like pneumospheres (P < 0.0001), significantly promoted by stimulation with soluble PD-L1 (27% ± 4, P < 0.0001) and inhibited by PD-1 blockade (-30% ± 3, P < 0.0001). The intravenous monotherapy with anti-PD-1 significantly inhibited tumor growth of NSCLC xenografts in immunodeficient mice, without the contribution of the immune system, and delayed the occurrence of chemoresistance when combined with cisplatin. We report first evidence of a novel lymphocyte-independent activity of anti-PD-1 antibodies in NSCLC, capable of inhibiting chemo-surviving NSCLC cells and exploitable to contrast disease relapses following chemotherapy. See related commentary by Augustin et al., p. 505.

Recent advances in sterilization and disinfection technology A review.

Sterilization and disinfection of pollutants and microorganisms have been extensively studied in order to address the problem of environmental contamination, which is a crucial issue for public health and economics. Various form of hazardous materialspollutants including microorganisms and harmful gases are released into the environment that enter into the human body either through inhalation, adsorption or ingestion. The human death rate rises due to various respiratory ailments, strokes, lung cancer, and heart disorders related with these pollutants. Hence, it is essential to control the environmental pollution by applying economical and effective sterilization and disinfections techniques to save life. In general, numerous forms of traditional physical and chemical sterilization and disinfection treatments, such as dry and moist heat, radiation, filtration, ethylene oxide, ozone, hydrogen peroxide, etc. are known along with advanced techniques. In this review we summarized both advanced and conventional techniques of sterilization and disinfection along with their uses and mode of action. This review gives the knowledge about the advantages, disadvantages of both the methods comparatively. Despite, the effective solution given by the advanced sterilization and disinfection technology, joint technologies of sterilization and disinfection has proven to be more effective innovation to protect the indoor and outdoor environments.

Average uranium bedrock concentration in Swedish municipalities predicts male lung cancer incidence rate when adjusted for smoking prevalence Indication of a cumulative radon induced detriment.

Bedrock U has been used as a proxy for local indoor radon exposure. A preliminary assessment of cancer incidence rate in a cohort of 809,939 adult males living in 9 different Swedish counties in 1986 has been used to correlate the cumulative lung cancer and total cancer (excluding lung) incidence rates between 1986 and 2020, respectively with the municipality average value of bedrock U concentration obtained from Swedish geological Survey (SGU). To control for regional difference in tobacco smoking, data on county average smoking prevalence, obtained from a survey conducted by the Public Health Agency of Sweden from 2001 to 2004, was used. Regression analysis shows that there is a significant positive correlation between smoking prevalence adjusted lung cancer incidence rate in males and the municipality bedrock U concentration (R

Global magnitude and temporal trend of mesothelioma burden along with the contribution of occupational asbestos exposure in 204 countries and territories from 1990 to 2019 Results from the Global Burden of Disease Study 2019.

Understanding the burden of mesothelioma with the contribution of occupational asbestos exposure globally provides essential foundations for cancer control, policy decisions and resource allocation. Globally, 34,511 incident cases, 29,251 deaths and 668,104 disability-adjusted life years (DALYs) of mesothelioma were estimated in 2019. The age-standardized rates of incidence, mortality and DALYs all showed a slightly declining trend over the past 30 years, but the latest absolute number of mesothelioma burden almost doubled since 1990. The burden rate decreased among the population aged under 70 years, but increased among the population aged over 80 years, especially in the High socio-demographic index (SDI) region. The burden rate of mesothelioma attributable to asbestos exposure was positively associated with SDI at the national level. This study depicted a continuous increase in mesothelioma burden globally over the past 30 years. Controlling occupational asbestos exposure will reduce the mesothelioma burden, especially for higher SDI regions.

Proceedings of the 2022 National Toxicology Program Satellite Symposium.

The 2022 annual National Toxicology Program Satellite Symposium, entitled Pathology Potpourri, was held in Austin, Texas at the Society of Toxicologic Pathologys 40th annual meeting during a half-day session on Sunday, June 19. The goal of this symposium was to present and discuss challenging diagnostic pathology andor nomenclature issues. This article presents summaries of the speakers talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included induced and spontaneous neoplastic and nonneoplastic lesions in the mouse lung, spontaneous lesions in the reproductive tract of a female cynomolgus macaque, induced vascular lesions in a mouse asthma model and interesting case studies in a rhesus macaque, dog and genetically engineered mouse model.

N6-methyladenosine in hematological malignancies a concise review.

Hematological malignancies are a kind of systemic cancers mostly related to abnormal differentiation of blood stem cells. Because of the poor prognosis, chemotherapy resistance and common recurrence, new mechanisms and treatment therapies are looking forward to be discovered. Over the years, epigenetic abnormalities have been known to act a key part in occurrence and development of hematological tumors. In the internal modifications on long noncoding eukaryotic mRNA, there is a common type called N6-methyladenosine that can change the expression of target genes and participate in the translation, degradation and splicing of mRNA. M6A is related to a wealth of cancers, such as HNRNPA2B1s elevation in multiple myeloma, METTLE3s elevation in acute myeloid leukemia and lung cancer. Immune cells, playing a significant role in hematological cancers, can also be regulated by m6A. In the review, we summarized the recent progress on hematological malignancies associating with m6A and immune cells, which may offer a new road for the treatment of them.

Preoperative MRI-Based Radiomics of Brain Metastasis to Assess T790M Resistance Mutation After EGFR-TKI Treatment in NSCLC.

Preoperative assessment of the acquired resistance T790M mutation in patients with metastatic non-small cell lung cancer (NSCLC) based on brain metastasis (BM) is important for early treatment decisions. To investigate preoperative magnetic resonance imaging (MRI)-based radiomics for assessing T790M resistance mutation after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment in NSCLC patients with BM. Retrospective. One hundred and ten primary NSCLC patients with pathologically confirmed BM and T790M mutation status assessment from two centers divided into primary training (N 53), internal validation (N 27), and external validation (N 30) sets. Contrast-enhanced T1-weighted (T1CE) and T2-weighted (T2W) fast spin echo sequences at 3.0 T. Forty-five (40.9%) patients were T790M-positive and 65 (59.1%) patients were T790M-negative. The tumor active area (TAA) and peritumoral edema area (POA) of BM were delineated on pre-treatment T1CE and T2W images. Radiomics signatures were built based on features selected from TAA (RS-TAA), POA (RS-POA), and their combination (RS-Com) to assess the T790M resistance mutation after EGFR-TKI treatment. Receiver operating characteristic (ROC) curves were used to assess the capabilities of the developed RSs. The area under the ROC curves (AUC), sensitivity, and specificity were generated as comparison metrics. We identified two features (from TAA) and three features (from POA) that are highly associated with the T790M mutation status. The developed RS-TAA, RS-POA, and RS-Com showed good performance, with AUCs of 0.807, 0.807, and 0.864 in the internal validation, and 0.783, 0.814, and 0.860 in the external validation sets, respectively. Pretreatment brain MRI of NSCLC patients with BM might effectively detect the T790M resistance mutation, with both TAA and POA having important values. The multi-region combined radiomics signature may have potential to be a new biomarker for assessing T790M mutation. 3 TECHNICAL EFFICACY Stage 2.

Allergen immunotherapy, cancer, and immune disorders.

The purpose of this review is to provide an update on the intriguing relationships between allergies, allergen immunotherapy, cancer, and immune disorders. Allergic diseases and cancer are increasing in incidence and prevalence and a potential relationship, or not, between these diseases have been suggested for many years. Recent findings suggest that there may be some causative effects between certain types of cancer and allergic diseases, as described in the text. Some types of cancer may be more linked to the presence of an allergic disease, than others. However, epigenetic factors, such as tobacco smoke alcohol and toxic substances should also be taken into consideration. The association between allergy and cancer is complex and depends on the specific allergy and the specific organ under consideration. Regarding pancreatic cancer, colorectal cancer (CRC), and glioma, all types of allergies were shown to be a protective factor. Conversely, asthma is a risk factor for lung cancer as is atopic dermatitis for skin cancer. Despite extensive research, no definite relationship has been determined, and no clear relationship, either positive or negative, to allergies can be observed. These results should be corroborated with large epidemiological well designed prospective studies due to some weaknesses in the previous investigations.

Outcome of non-small-cell lung cancer with driven mutations treated with anti-PD-(L)1 agents A systematic review.

Patients whose tumours harbour epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) driver mutations can benefit most from treatment with tyrosine kinase inhibitors (TKIs). Most trials with immune checkpoint inhibitors (ICIs) included few patients whose tumour had oncogenic driver alterations. We therefore performed a meta-analysis of studies reporting the activity of ICIs in oncogene addicted NSCLC. A comprehensive search of MEDLINE, The Cochrane Library and EMBASE was conducted to identify relevant studies published up to 31 January 2021. The primary outcomes were median overall survival (OS) the secondary endpoints were progression-free survival and overall response rate (PFS and ORR). Overall, 46 studies were screened and selected for final analysis. The pooled ORR was 14.5% (95% CI 9.6-21.2%). The median pooled PFS in EGFRALK mutated cases was 3.9 months (95% CI 3-5.2 months). Median pooled OS was 10.7 months (95% CI 9.2-12.5 months). All registration trials in second line did not show any benefit of immunotherapy for the subgroup of patients with EGFR-mutated or ALK-rearranged tumours. The unsatisfied benefit of immunotherapy in oncogene-addicted tumours has been debated and is mainly due to the lower mutation burden of these neoplasms. Our data do not support the use of immunotherapy in the setting of oncogene actionable tumours. More data are needed to confirm or reject the benefit of the combination of TKIs with ICIs.

A plant-derived glucocorticoid receptor modulator with potency to attenuate the side effects of glucocorticoid therapy.

Continuous efforts have been made to move towards maintaining the beneficial anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. Here, we investigated the selective glucocorticoid receptor (GR) modulator-like properties of a plant-derived compound caesaldekarin e (CA-e). The therapeutic efficacy of CA-e was evaluated in several mouse models, including dextran sulfate sodium-induced colitis, ovalbumin-induced lung allergic inflammation, imiquimod-induced psoriasis-like skin inflammation and skin atrophy. The action of CA-e targeting the GR was analysed using molecular docking, cellular thermal shift assays and microscale thermophoresis. Other methods included DNA-protein pull-down assays and mass spectrometry. CA-e selectively inhibited positive GC response element (() GRE)-mediated direct transactivation while maintaining and even enhancing the anti-inflammatory effects of treatment with dexamethasone. CA-e, alone and in combination with dexamethasone, efficiently alleviated inflammation in several mouse models with milder side effects compared with dexamethasone alone. Mechanistically, CA-e inhibited the formation of dimers by binding to the dimerization interface located in the ligand-binding domain of GR and facilitated embryonic ectoderm development that is involved in the regulation of transcriptional repression to compete for binding to () GRE, eventually leading to the repression of () GRE-regulated genes. In addition, CA-e repressed NF-κB-dependent genes by enhancing the interaction between GR and p65. Our results reveal that CA-e is a novel GR modulator with strong potency to attenuate the side effects of GC therapy and can be used as a potential molecular tool for deciphering GR signalling.

Identification of Immune Infiltration and Effective Immune Biomarkers in Acute Lung Injury by Bioinformatics Analysis.

Acute lung injury (ALI) is a serious complication in clinical settings. This study aimed to elucidate the immune molecular mechanisms underlying ALI by bioinformatics analysis. Human ALI and six ALI mouse model datasets were collected. Immune cell infiltration between the ALI samples and non-ALI controls was estimated using the ssGSEA algorithm. Least absolute shrinkage and selection operator (LASSO) regression analysis and Wilcoxon test were performed to obtain the significantly different immune cell infiltration types. Immune feature genes were screened by differential analysis and the weighted correlation network analysis (WGCNA) algorithm. Functional enrichment was then performed and candidate hub biomarkers were identified. Finally, the receiver operator characteristic curve (ROC) analysis was used to predict their diagnostic performances. Three significantly different immune cell types (B cells, CD4 T cells, and CD8 T cells) were identified between the ALI samples and controls. A total of 13 immune feature genes were obtained by WGCNA and differential analysis and found to be significantly associated with immune functions and lung diseases. Four hub genes, including CD180, CD4, CD74, and MCL1 were identified using cytoHubba and were shown to have good specificity and sensitivity for the diagnosis of ALI. Correlation analysis suggested that CD4 was positively associated with T cells, whereas MCL1 was negatively correlated with B and T cells. We found that CD180, CD4, CD74, and MCL1 can serve as specific immune biomarkers for ALI. MCL1-B cell, MCL1-T cell, and CD4-T cell axes may be involved in the progression of ALI.

Loss of apelin blocks the emergence of sprouting angiogenesis in experimental tumors.

Angiogenesis inhibitor drugs targeting vascular endothelial growth factor (VEGF) signaling to the endothelial cell (EC) are used to treat various cancer types. However, primary or secondary resistance to therapy is common. Clinical and pre-clinical studies suggest that alternative pro-angiogenic factors are upregulated after VEGF pathway inhibition. Therefore, identification of alternative pro-angiogenic pathway(s) is critical for the development of more effective anti-angiogenic therapy. Here we study the role of apelin as a pro-angiogenic G-protein-coupled receptor ligand in tumor growth and angiogenesis. We found that loss of apelin in mice delayed the primary tumor growth of Lewis lung carcinoma 1 and B16F10 melanoma when combined with the VEGF receptor tyrosine kinase inhibitor, sunitinib. Targeting apelin in combination with sunitinib markedly reduced the tumor vessel density, and decreased microvessel remodeling. Apelin loss reduced angiogenic sprouting and tip cell marker gene expression in comparison to the sunitinib-alone-treated mice. Single-cell RNA sequencing of tumor EC demonstrated that the loss of apelin prevented EC tip cell differentiation. Thus, apelin is a potent pro-angiogenic cue that supports initiation of tumor neovascularization. Together, our data suggest that targeting apelin may be useful as adjuvant therapy in combination with VEGF signaling inhibition to inhibit the growth of advanced tumors.

Prognostic value of

Adaptation criterion for segmentectomy in small-sized early stage non-small cell lung cancer.

Although the utility of segmentectomy for early-stage non-small cell lung cancer (NSCLC) has been reported, the adaptation criterion for segmentectomy is unclear. In total, 171 NSCLC patients who underwent segmentectomy or lobectomy with a consolidation tumor diameter on computed tomography of ≤20 mm were analyzed. Consolidation diameter (p 0.01), consolidation to tumor ratio (CTR) (p < 0.01), maximum standardized uptake value (SUV Consolidation tumor diameter on CT, CTR, and SUV

Transcription Factor Sp1 in the Expression of Genes Encoding Components of MAPK, JAKSTAT, and PI3KAkt Signaling Pathways.

Sp1 is a transcription factor of the SpKLF family that binds to GC-rich motifs in regulatory regions of genes. Sp1 is involved in the regulation of cell proliferation, apoptosis and differentiation, and angiogenesis. A high level of SP1 expression, as well as its aberrant transcriptional activity due to post-translational modifications, is found in cells in oncological diseases, such as lung, breast, pancreatic, thyroid, gastric cancer, and glioma congenital heart disease, as well as neurodegenerative disorders, including Huntingtons and Parkinsons diseases. Binding of Sp1 to GC-rich motifs of the regulatory regions of the genes encoding components of the MAPK, p38, JAKSTAT, PI3KAkt signaling pathways, is involved in the control of cell proliferation, differentiation, and death. In addition, kinases of these signaling pathways are able to change the transcriptional activity of Sp1 by phosphorylation of certain amino acid residues, which leads to a change in the efficiency of its binding to cofactors and DNA regulatory regions. This review presents data on the relationship between the Sp1 transcription factor and the activity of the MAPK, p38, JAKSTAT, and PI3KAkt signaling pathways in normal tissues and in various pathologies, including malignant diseases.

Mechanism of Cordyceps militaris against non-small cell lung cancer based on serum metabolomics.

This study investigated the potential mechanism of Cordyceps militaris(CM) against non-small cell lung cancer(NSCLC) based on serum untargeted metabolomics. Specifically, Balbc nude mice were used to generate the human lung cancer A549 xenograft mouse model. The tumor volume, tumor weight, and tumor inhibition rate in mice in the model, cisplatin, Cordyceps(low-, medium-, and high-dose), and CM(low-, medium-, and high-dose) groups were compared to evaluate the influence of CM on lung cancer. Gas chromatography-mass spectrometry(GC-MS) was used for the analysis of mouse serum, SIMCA 13.0 for the compa-rison of metabolic profiles, and MetaboAnalyst 5.0 for the analysis of metabolic pathways. According to the pharmacodynamic data, the tumor volume and tumor weight of mice in high-dose CM group and cisplatin group decreased as compared with those in the model group(Plt0.05 or Plt0.01). The results of serum metabolomics showed that the metabolic profiles of the model group were significantly different from those of the high-dose CM group, and the content of endogenous metabolites was adjusted to different degrees. A total of 42 differential metabolites and 7 differential metabolic pathways were identified. In conclusion, CM could significantly inhibit the tumor growth of lung cancer xenograft mice. The mechanism is the likelihood that it influences the aminoacyl-tRNA biosynthesis, the metabolism of D-glutamine and D-glutamate, metabolism of alanine, aspartate, and glutamate, metabolism of glyoxylate and dicarboxylic acid, biosynthesis of phenylalanine, tyrosine, and tryptophan, arginine biosynthesis as well as nitrogen metabolism. This study elucidated the underlying mechanism of CM against NSCLC from the point of metabolites. The results would lay a foundation for the anticancer research and clinical application of CM.

Impact of the use of antibiotics on the clinical response to immune checkpoint inhibitors in patients with non-small cell lung cancer.

Recent research suggests that the use of antibiotics could reduce the efficacy of checkpoint inhibitors, in addition to other well-known factors. It could be due to gut microbiota modification, which impact over the immune system response. However, the information available so far is contradictory. The objective of this research was to clarify whether antibiotic use influences efficacy of checkpoint inhibitors treatments in non-small cell lung cancer patients in clinical practice. Therefore, a retrospective observational study was designed. Use of antibiotics among patients treated with atezolizumab, pembrolizumab or nivolumab was assessed within 2 months of checkpoint inhibitors treatments initiation. A total of 140 patients were included, mostly men, with good performance status (ECOG 0-1), all of them previously treated with chemotherapy. An antibiotic prescription was identified in 31% of these patients, mainly fluoroquinolones or beta-lactams. The most frequent indication was respiratory infection. Both progression-free survival and overall survival were lower for patients treated with anti-infective drugs, although this difference was not statistically significant. More studies are needed to draw conclusions about the impact of antibiotics on the efficacy of immunotherapy. Investigaciones recientes sugieren que el uso de antibióticos podría reducir la eficacia de los inhibidores del punto de control inmunológico, además de otros factores ya conocidos. Podría deberse a la modificación de la microbiota, por su impacto en la respuesta del sistema inmune. En cualquier caso, la información disponible hasta el momento es contradictoria. El objetivo de esta investigación es esclarecer si el uso de antibióticos influye en la eficacia de los inhibidores del punto de control para el tratamiento de pacientes con carcinoma de pulmón no microcítico en la práctica clínica. Se diseñó un estudio observacional, retrospectivo. Se investigó el uso de antibióticos entre aquellos pacientes a tratamiento con atezolizumab, pembrolizumab o nivolumab en los 2 meses previos o posteriores a su inicio. Se incluyeron 140 pacientes, principalmente hombres con aceptable estado general (ECOG 0-1), todos previamente tratados con quimioterapia. Se identificó una prescripción antibiótica en el 31% de la población, principalmente fluoroquinolonas o betalactámicos. La indicación más frecuente para dicha prescripción era la infección respiratoria. Tanto la supervivencia libre de progresión con la supervivencia global fue inferior en el grupo tratado con antiinfecciosos, aunque no se alcanzó significación estadística. Son necesario más estudios para concluir acerca del impacto de los antibióticos en la eficacia de la inmunoterapia.

Circular RNA hsacirc0018189 drives non-small cell lung cancer growth by sequestering miR-656-3p and enhancing xCT expression.

Non-small cell lung cancer (NSCLC) is one of the cancers with a high mortality rate. CircRNAs have emerged as an important regulatory factor in tumorigenesis in recent years. However, the detailed regulatory mechanism of a circular RNA cullin 2 (hsacirc0018189 hsacirc0018189) is still unclear in NSCLC. RNA levels of hsacirc0018189, microRNA (miR)-656-3p, and Solute carrier family seven member 11 (SLC7A11, xCT) were analyzed by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR), and protein level was assessed by Western blot and immunohistochemical assay. Enzyme-linked immunosorbent assay was conducted to detect cell glutamine metabolism. Effects of hsacirc0018189 on cell proliferation, apoptosis, migration, and invasion were analyzed by corresponding assays. Luciferase reporter assay and RNA-immunoprecipitation assay confirmed the target relationship between miR-656-3p and hsacirc0018189 or xCT. The in vivo function of hsacirc0018189 was verified by xenograft mouse models. Hsacirc0018189 abundance was overexpressed in NSCLC cells and samples. Deficiency of hsacirc0018189 lowered NSCLC cell proliferative, migrating, invading, and glutamine metabolism capacities, and hsacirc0018189 silencing inhibited the growth of tumors in vivo. Hsacirc0018189 could up-regulate xCT by sponging miR-656-3p. And miR-656-3p downregulation or xCT overexpression partly overturned hsacirc0018189 knockdown or miR-656-3p mimic-mediated repression of NSCLC cell malignancy. Hsacirc0018189 drove NSCLC growth by interacting with miR-656-3p and upregulating xCT.

Tumour, whole-blood, plasma and tissue concentrations of metformin in lung cancer patients.

Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results. Subjects with solid tumours to be treated by resection and either (A) willingness to take metformin for 7-10 days before surgery or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumour, tumour-adjacent uninvolved tissue and subcutaneous adipose tissue were obtained for liquid chromatography with tandem mass spectrometry to measure metformin concentrations. All subjects had primary lung tumours. Metformin dose was significantly correlated with drug concentrations in all tissues analysed. Intersubject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumour tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues. Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung and tumour tissues in subjects treated with US Food and Drug Administration-approved doses for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra-pharmacological doses of metformin. Given the large intersubject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anticancer activity in humans.

The influence of CT acquisition and reconstruction parameters on the stability of radiomic features of pure ground-glass nodules.

Effect of dNLR and LIPI scores on the prognosis of elderly patients with non-surgical treatment of non-small cell lung cancer.

Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer.

As a newly emerged class of anticancer bioagents in the most precise and selectively targeted way, antibody-drug conjugate (ADC) combines the cancer-targeting abilities of monoclonal antibodies with the cytotoxicity potency of payload, delivering highly cytotoxic drug into tumors via targeted chemotherapy. ADC has revolutionized the treatment landscape of human epidermal growth factor receptor 2 positive and triple negative subtypes in breast cancer. Three ADCs have been approved by U. S. Food and Drug Administration with breast cancer indications, including trastuzumab emtansine (T-DM1 also approved in China), trastuzumab deruxtecan (T-DXd, DS-8201) and sacituzumab govitecan (IMMU-132 also approved in China). Antibodies, cytotoxic drug, linker, and conjugation process are implicated in ADC profile, resulting in unique adverse drug reactions and toxicity heterogeneity within ADC class. For example, more attention should be paid to the management of thrombocytopenia, hepatotoxicity, and reductions in left ventricular ejection fraction (LVEF) in patients treated with trastuzumab emtansine clinical physicians should pay attention to the risk of neutropenia, interstitial lung diseasepneumonitis, and reductions in LVEF when treated with trastuzumab deruxtecan sacituzumab govitecan most frequently caused neutropenia, anemia and diarrhea requiring close monitor. ADC has generally favorable safety profiles, and dose modifications andor symptomatic supporting treatment are effective in terms of toxicity management. This consensus aims at providing guidance for clinical oncologists of early detection, regular assessment, timely management and follow-up monitor of ADC-associated adverse reactionsevents. 抗体药物偶联物(ADC)将单克隆抗体的选择性与有效载荷的细胞杀伤特性合二为一，通过靶向化疗的方式将细胞毒性药物释放至肿瘤，是一类相对新颖的具有高度靶向性的抗癌生物制剂。在乳腺癌领域中，ADC改变了人类表皮生长因子受体2阳性以及三阴性乳腺癌的治疗格局。目前获得美国食品药品监督管理局批准的3种ADC有乳腺癌适应证，分别为恩美曲妥珠单抗、Trastuzumab deruxtecan和戈沙妥珠单抗，其中恩美曲妥珠单抗和戈沙妥珠单抗也在中国获得批准上市。鉴于ADC涉及抗体、细胞毒性制剂、连接子以及偶联过程，因此导致了ADC不良反应的独特性及其类别内安全谱的异质性。接受恩美曲妥珠单抗治疗的患者需特别关注血小板减少、肝不良反应以及左心室射血分数(LVEF)降低；Trastuzumab deruxtecan治疗期间应关注中性粒细胞减少、间质性肺疾病或非感染性肺炎以及LVEF降低的风险；戈沙妥珠单抗治疗常导致中性粒细胞减少、贫血，同时需密切监测腹泻。ADC总体上安全性良好，剂量调整和(或)对症支持治疗为有效的管理方式。中国医师协会肿瘤医师分会乳腺癌学组和中国抗癌协会国际医疗交流分会组织专家共同制定了中国乳腺癌抗体药物偶联物安全性管理专家共识，旨在为临床肿瘤医师提供ADC相关不良反应或不良事件的早期识别、定期评估、及时管理以及随访监测的实践指导。.

DDX17 modulates the expression and alternative splicing of genes involved in apoptosis and proliferation in lung adenocarcinoma cells.

The DEAD-box RNA-binding protein (RBP) DDX17 has been found to be involved in the tumorigenesis of many types of cancers. However, the role of DDX17 in lung adenocarcinoma (LUAD) remains unclear. We silenced DDX17 expression in A549 LUAD cells by small interfering RNA (siRNA). Cell proliferation and apoptosis assays were performed to explore the functions of DDX17. Knockdown of DDX17 by siRNA significantly inhibited proliferation and induced apoptosis in A549 cells. We used high-throughput RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs) and alternative splicing (AS) events in DDX17 knockdown LUAD cells. DDX17 knockdown increased the expression levels of proapoptotic genes and decreased those of proproliferative genes. Moreover, the DDX17-regulated AS events in A549 cells revealed by computational analysis using ABLas software were strongly validated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and were also validated by analysis of The Cancer Genome Atlas (TCGA)-LUAD dataset. These findings suggest that DDX17 may function as an oncogene by regulating both the expression and AS of proliferation- and apoptosis-associated genes in LUAD cells. Our findings may offer new insights into understanding the molecular mechanisms of LUAD and provide a new therapeutic direction for LUAD.

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNKP38 MAPK pathway in a rat model.

Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), used for the treatment of advanced or metastatic non-small cell lung cancer. Recently, studies proved that Gefitinib-induced cardiotoxicity through induction of oxidative stress leads to cardiac hypertrophy. The current study was conducted to understand the mechanisms underlying gefitinib-induced cardiac hypertrophy through studying the roles of angiotensin II (AngII), oxidative stress, and mitogen-activated protein kinase (MAPK) pathway. Male Wistar albino rats were treated with valsartan, gefitinib, or both for four weeks. Blood samples were collected for AngII and cardiac markers measurement, and hearts were harvested for histological study and biochemical analysis. Gefitinib caused histological changes in the cardiac tissues and increased levels of cardiac hypertrophy markers, AngII and its receptors. Blocking of AngII type 1 receptor (AT1R) via valsartan protected hearts and normalized cardiac markers, AngII levels, and the expression of its receptors during gefitinib treatment. valsartan attenuated gefitinib-induced NADPH oxidase and oxidative stress leading to down-regulation of JNKp38-MAPK pathway. Collectively, AT1R blockade adjusted AngII-induced NADPH oxidase and JNKp38-MAPK leading to attenuation of gefitinib-induced cardiac hypertrophy. This study found a pivotal role of AngIIAT1R signaling in gefitinib-induced cardiac hypertrophy, which may provide novel approaches in the management of EGFRIs-induced cardiotoxicity.

Immune checkpoint inhibitors and potential risk of thromboembolic events Analysis of the WHO global database of individual case safety reports.

Thromboembolic events with the use of immune checkpoint inhibitors (ICIs) in patients with cancer have been reported in few studies. However, the detailed profile of these cases remains mostly uncertain. A descriptive analysis of Thromboembolic events associated with ICIs retrieved from the VigiBase, between 1967 to November 2020. We extracted the data using the terms of pulmonary embolism OR deep vein thrombosis OR acute coronary syndrome OR myocardial infarction OR ischemic stroke (preferred term (PT) (MedDRA). We included 161 cases from 26 countries in our descriptive analysis. Patients ages were reported in 141 (87.6%) cases, with a median of 68 years (interquartile range 61-74), and 63.4% of the patients were male. Indications for ICIs were reported in 151 (93.8%) cases, as follows lung cancer (n 85, 52.8%), renal cell carcinoma (n 24, 14.9%), melanoma (n 20, 12.4%), urethral carcinoma (n 12, 7.45%), breast cancer (n 4, 2.48%), adenocarcinoma of the gastroesophageal junction (n 3, 1.9%), gastric cancer (n 2, 1.24%), and skin cancer (n 1, 0.62%). Nivolumab was reported as a suspected drug in 76 cases (47%), pembrolizumab in 46 cases (28.5%), atezolizumab in 21 cases (13%), durvalumab in 14 cases (8.6%), and avelumab in four cases (2.4%).The time to onset of thromboembolic events was reported in 127 (78.8%) cases. Most of these patients (n 109, 85.8%) reported thromboembolic events within the first six months. The causality assessment of included cases showed that 50.3% of reported thromboembolic events were possibly related to the suspected reported medication, 13.7% were probably related, 13% were unlikely to be related, and 23% were not assessable due to insufficient information. This study demonstrates a possible association between the use of ICIs and thromboembolic events. Further epidemiological studies are needed to assess this association and to elucidate the underlying mechanism.

In silico prediction of COVID-19 cytokine storm in lung cancer types.

Lung cancer is one of the most frequently diagnosed malignant tumors and the leading cause of cancer-related death worldwide. Mainly, Non-small-cell lung cancer (NSCLC), which accounts for more than eighty-five percent of all lung cancers, consists of two major subtypes lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Novel coronavirus disease (COVID-19) affected millions of people caused by acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) around the globe. Lung cancer patients and COVID-19 present unique and unfortunate lethal combinations because the lungs are the primary target organ of SARS-CoV-2 infection. Clinical studies have demonstrated that an over-activated inflammatory response associated with severe COVID-19 cases is characterized by excessive auto-amplifying cytokine release, which is defined as a cytokine storm. ACE2 and TMPRSS2 receptors play an essential role in SARS-CoV-2 infection therefore, using in silico analysis, we did correlation analysis with immune infiltration markers in LUAD and LUSC patient groups. Our study identified a promising correlation between immune-modulators and receptor proteins (ACE-2 and TMPRSS2), creating a domain that requires further laboratory studies for clinical authentication.

Effect of Quality Control Circle Activity Nursing Combined with Respiratory Function Exercise Nursing on Patients with Esophageal Cancer.

To explore the effect of quality control circle activity nursing combined with respiratory function exercise nursing on esophageal cancer patients immune function and nutritional status. The clinical case data of 119 esophageal cancer patients admitted to our hospital were selected as the research objects from May 2019 to July 2021. They were divided into the quality control circle activity care group (QCCAC) (9 cases dropped due to incomplete case data, n 50) and respiratory function exercise care group (10 cases dropped due to incomplete case data, n50) by the random number table method, the respiratory function exercise care group was treated with respiratory function exercise care, while the QCCAC group was treated with QCCAC. Changes in lung function, immune function, and nutritional status before and after nursing were compared in the two groups of patients. Before nursing, there was no significant difference in pulmonary function indexes, immune function indexes, and the level of nutritional status indicators between the two groups ( Quality control circle activity nursing combined with respiratory function exercise nursing can effectively improve the immune function, respiratory function, and nutritional status of esophageal cancer patients.

Late recurrence of late-onset large cell calcifying Sertoli tumor successfully managed by early surgical intervention.

Large cell calcifying Sertoli tumor is an uncommon testicular neoplasm. We present a case of a 36-year-old man with a late-onset large cell calcifying Sertoli tumor that resulted in a solitary lung metastasis 5 years after radical orchiectomy. Pulmonary wedge resection was performed, and there was no recurrence at the 18-month follow-up after resection of the lung metastasis. Because of its malignant potential, late-onset large cell calcifying Sertoli tumor requires long-term follow-up.

A review of venous reconstruction options for the mediastinum.

Major vessels of the mediastinum such as the superior vena cava (SVC) and bilateral innominate veins can occasionally become involved with aggressive tumors or the mediastinum, including non-small cell lung cancer and thymoma. This may result in partial or complete obstruction. With presentation of these tumors symptoms can often be debilitating and would otherwise be treated with palliative therapy. A select population of patients are candidates for tumor resection. The ability to perform an adequate resection will depend on the ability to create a durable reconstruction of the SVC and bilateral innominate veins. Pre-operative and intra-operative considerations will allow for a safe surgery with few complications to the patient. Furthermore, depending on the extent of resection, there are a variety of techniques for reconstruction. These can range from a primary repair of a partial venous wall resection to a complex replacement of both the SVC and one or both innominate veins. Multiple options exist for the use of these conduits, such as polytetrafluoroethylene, homograft, autologous vein, and bovine or porcine pericardium. Depending on the type of conduit used, the post-operative outcomes will differ. In order to perform this operation safely, proper knowledge and experience is required. We review a variety of strategies used to manage these rare but complex scenarios.

CXC Chemokines in the Pathogenesis of Pulmonary Disease and Pharmacological Relevance.

Chemokines and their receptors play important roles in the pathophysiology of many diseases by regulating the cellular migration of major inflammatory and immune players. The CXC motif chemokine subfamily is the second largest family, and it is further subdivided into ELR motif CXC (ELR) and non-ELR motif (ELR-) CXC chemokines, which are effective chemoattractants for neutrophils and lymphocytesmonocytes, respectively. These chemokines and their receptors are expected to have a significant impact on a wide range of lung diseases, many of which have inflammatory or immunological underpinnings. As a result, manipulations of this subfamily of chemokines and their receptors using small molecular agents and other means have been explored for potential therapeutic benefit in the setting of several lung pathologies. Furthermore, encouraging preclinical data has necessitated the progression of a few of these drugs into clinical trials in order to make the most effective use of interventions in the development of viable targeted therapeutics. The current review presents the understanding of the roles of CXC ligands (CXCLs) and their cognate receptors (CXCRs) in the pathogenesis of several lung diseases such as allergic rhinitis, COPD, lung fibrosis, lung cancer, pneumonia, and tuberculosis. The potential therapeutic benefits of pharmacological or other CXCLCXCR axis manipulations are also discussed.

Bronchorrhea, a Rare and Debilitating Symptom of Lung Cancer Case Report and Review of the Treatment.

Bronchorrhea, defined as production of voluminous watery sputum greater than 100 mLd, is a debilitating symptom mostly found in end-stage lung cancer, specifically in invasive mucinous adenocarcinomas. Very rarely, it can primarily contribute to hypoxic respiratory failure and found in a critical care setting. We report a case of a 51-year-old woman diagnosed with having mucinous adenocarcinoma of the lung who presented to the intensive care unit with rapidly worsening respiratory failure and found to have massive bronchorrhea with daily sputum volume exceeding 1000 mLd at its peak. With the limited quantity and quality of evidence available for the treatment of this condition, multiple agents were tried without considerable benefit. We discuss the pathogenesis of this condition and the different treatment options that can be used for palliation of the sputum volume.

The Clinical Significance of Deglycosylated PD-L1 Level Detection Using 28-8 Monoclonal Antibody in Lung Adenocarcinoma.

The aim of this study was to explore the clinical significance of deglycosylated PD-L1 level and its correlation with EGFR and ALK mutation in lung adenocarcinoma. We estimated the intensity of both native and deglycosylated PD-L1 signals using a 28-8 antibody on lung adenocarcinoma tissue microarray sections. We analyzed the difference in the H-score between tumor and paratumor tissues, as well as that before and after deglycosylation. Correlations between EGFR or ALK status and PD-L1 expression were analyzed. We also evaluated the differences among survival curves. The expression level of PD-L1 in lung adenocarcinoma tissues was significantly higher than that in paratumor tissues (P<0.0001). Deglycosylation significantly enhanced the detection of PD-L1 in tumor tissues (P<0.0001). There was no statistical significance between the signal intensity of deglycosylated PD-L1 and the survival of patients (P0.9099). However, the response to deglycosylation of PD-L1 was significantly correlated with the survival of patients with stage N1-N3 (P0.0435) and stage T3-T4 (P0.0366) and male patients (P0.0258). A statistical trend was found in the correlation between the response to deglycosylation of PD-L1 and the survival of patients with grade II-III plus grade III (P0.0973). Correlation between EGFR or ALK status and the expression of PD-L1 was not found (P>0.05). PD-L1 deglycosylation enhances the detection of PD-L1 when utilizing a 28-8 antibody. Moreover, the response to deglycosylation of PD-L1 may predict the survival of certain patients with lung adenocarcinoma.

MPN-092 Paraneoplastic Eosinophilia An Unusual Initial Presentation of Metastatic Pancreatic Adenocarcinoma.

Paraneoplastic eosinophilia is mainly associated with hematologic malignancies. It has been reported in solid tumors through case reports. Among solid tumors, hypereosinophilia was mainly described in melanoma and lung, renal, and thyroid carcinomas. We report the case of a 58-year-old female patient, a previously healthy heavy smoker who presented with worsening abdominal pain and dyspnea. Laboratory tests revealed hypereosinophilia with an absolute eosinophilic count (AEC) of 65,000mm

Integrating

The incidence of radiation pneumonitis (RP) has a highly linear relationship with low-dose lung volume. We previously established a volume-based algorithm (VBA) method to improve low-dose lung volume in radiotherapy (RT). This study assessed lung inflammatory changes by integrating fluorine-18-fluorodeoxyglucose positron emission tomographycomputed tomography ( Thirty esophageal cancer patients received Eleven patients in the nRP group and 19 patients in the RP group were identified. In 30 RP lungs, post-RT SUVmax, SUVmean and GLG of HD regions showed significant increases compared to values for pre-RT lungs. There were no significant differences in values of 22 nRP lungs. Post-RT SUVmax and SUVmean of HD regions, MLD, and lung V This study successfully integrated

The TCR repertoire diversity and its application in the prevention and treatment of lung cancer.

Immune checkpoint inhibitors have become the standard for advanced lung cancer treatment, but their effect on the prevention of lung cancer metastasis is still unclear. T-cell receptors (TCRs) are key signal sensors that recognize neoantigens on the surface of cancer cells. This review summarizes the research progress of TCR-T cell therapy in the prevention and treatment of lung cancer from the perspective of the diversity of TCR repertoire and the mechanism of tumor antigen recognition, in order to improve the efficacy of the prevention and treatment of lung cancer metastasis.

Case report identification of EGFR R776H and FANCE R381H germline mutations in a patient with multiple pulmonary nodules.

Pulmonary nodules evaluation is clinically crucial because they may be the early predictors of lung cancer. Except for CT screening and serum tumor biomarkers testing, genetic alteration analysis by next-generation sequencing (NGS) technology can also help to find cancer earlier. In this study, we report a case of multiple pulmonary nodules patient with EGFR R776H and FANCE R381H germline mutations. Her father, paternal aunt, and elder uncle harbored either one or both two mutations and were found with multiple pulmonary ground-glass or sub-solid nodules. Her 7-year-old daughter also inherited the same two mutations.

Retention index of FDG-PETCT SUVmax of the primary tumor in non-small cell lung cancer as a predictor of lymph node metastasis a retrospective study.

Accurate staging of non-small cell lung cancer is key in treatment planning and prediction of prognosis. We investigated the correlation between the maximum standardized uptake value (SUVmax) retention index (RI) of the primary tumor and lymph node metastasis in non-small cell lung carcinoma. We also evaluated the tendencies according to the histological types. We retrospectively evaluated 218 non-small cell lung cancer (NSCLC) tumors from 217 patients who underwent preoperative fluorodeoxyglucose-positron emission tomographycomputed tomography (PETCT) followed by lung surgery and lymph node resection between July 2015 and August 2020. All primary tumors were calculated as the SUVmax at 50 min (SUVmax The median SUVmax The RI of primary NSCLC tumors can help predict lymph node metastases, particularly in patients with adenocarcinoma.

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer a bioinformatics analysis and literature review.

Coronavirus disease 2019 (COVID-19) poses a serious threat to human health and life. The effective prevention and treatment of COVID-19 complications have become crucial to saving patients lives. During the phase of mass spread of the epidemic, a large number of patients with pulmonary fibrosis and lung cancers were inevitably infected with the SARS-CoV-2 virus. Lung cancers have the highest tumor morbidity and mortality rates worldwide, and pulmonary fibrosis itself is one of the complications of COVID-19. Idiopathic lung fibrosis (IPF) and various lung cancers (primary and metastatic) become risk factors for complications of COVID-19 and significantly increase mortality in patients. Therefore, we applied bioinformatics and systems biology approaches to identify molecular biomarkers and common pathways in COVID-19, IPF, colorectal cancer (CRC) lung metastasis, SCLC and NSCLC. We identified 79 DEGs between COVID-19, IPF, CRC lung metastasis, SCLC and NSCLC. Meanwhile, based on the transcriptome features of DSigDB and common DEGs, we identified 10 drug candidates. In this study, 79 DEGs are the common core genes of the 5 diseases. The 10 drugs were found to have positive effects in treating COVID-19 and lung cancer, potentially reducing the risk of pulmonary fibrosis.

ADRB2 expression predicts the clinical outcomes and is associated with immune cells infiltration in lung adenocarcinoma.

The gene encoding beta2-adrenergic receptor (β2-AR), adrenoceptor beta 2 (ADRB2), has been reported to closely associated with various cancers. However, its role in lung adenocarcinoma (LUAD) remains controversial. This research shed light on the prognostic value of ADRB2 in LUAD and further explored its association with immune cell infiltration. ADRB2 was significantly decreased in LUAD. ADRB2 expression in LUAD was significantly correlated with gender, smoking status, T classification, and pathologic stage. Patients in the low ADRB2 expression group presented with significantly poorer overall survival (OS) and disease-specific survival (DSS). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) results showed that ADRB2 participates in immune response. The expression of ADRB2 was positively correlated with the infiltration level of most immune cells. Notably, ADRB2 is involved in LUAD progression partly by regulating the immune microenvironment, which may potentially serve as a significant prognostic biomarker as well as a potential drug target.

Airway basal cells show a dedifferentiated KRT17

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study, we focus on the properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing (scRNAseq) of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17

RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.

Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response to treatment, presumably due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in LUAD. We report evidence of RAS pathway oncogenic activation in 84% of LUAD, including 65% KRAS wild-type tumours, falling into four groups characterised by coincident alteration of STK11LKB1, TP53 or CDKN2A, suggesting that the classifications developed when considering only KRAS mutant tumours have significance in a broader cohort of patients. Critically, high RAS activity patient groups show adverse clinical outcome and reduced response to chemotherapy. Patient stratification using oncogenic RAS transcriptional activity instead of genetic alterations could ultimately assist in clinical decision-making.

Country of birth and non-small cell lung cancer incidence, treatment, and outcomes in New South Wales, Australia a population-based linkage study.

To compare treatment within 12 months of diagnosis, and survival by country of birth for people diagnosed with invasive non-small cell lung cancer (NSCLC) in New South Wales (NSW), Australia. A population-based cohort study of NSW residents diagnosed with NSCLC in 2003-2016 using de-identified linked data from the NSW Cancer Registry, NSW Admitted Patient Data collection, Emergency Departments, Medicare Benefits and Pharmaceutical Benefits Scheme, and National Death Index. Odds of receiving any treatment, surgery, systemic therapy, or radiotherapy respectively, in the 12 months following diagnosis were calculated using multivariable logistic regression. The hazard of death (all-cause) at one- and five-years following diagnosis was calculated using multivariable proportional hazards regression. 27,114 People were recorded with NSCLC in the 14-year study period. Higher percentages of older males from European countries applied in the earlier years, with a shift to younger people from South East Asia, New Zealand, and the Middle East. Adjusted analyses indicated that, compared with the Australian born, people from European countries were more likely to receive treatment, and, specifically surgery. Also, people from Asian countries were more likely to receive systemic therapy but less likely to receive radiotherapy. Survival at one- and five-years following diagnosis was higher for people born in countries other than Australia, New Zealand the United Kingdom and Germany. Variations exist in treatment and survival by country of birth in NSW. This may be affected by differences in factors not recorded in the NSW Registry, including use of general health services, family histories, underlying health conditions, other intrinsic factors, and cultural, social, and behavioural influences.

Stereotactic radiosurgery for post operative brain metastasic surgical cavities a single institution experience.

The standard therapy for brain metastasis was surgery combined with whole brain radiotherapy (WBRT). The latter is however, associated with important neurocognitive toxicity. To reduce this toxicity, postoperative stereotactic radiosurgery (SRS) is a promising technique. We assessed the efficacy and the tolerance to postoperative Gamma Knife radiosurgery (GK) on the tumor bed after resection of brain metastases. Between February 2011 and December 2016, following macroscopic complete surgical resection, 64 patients and 65 surgical cavities were treated by GK in our institution. The indication for adjuvant radiosurgery was a multidisciplinary decision. The main assessment criteria considered in this study were local control, intracranial metastasis-free survival (ICMFS), overall survival and toxicity. Median follow-up 11.1 months. Median time between surgery and radiosurgery 35 days. Median dose was 20 Gy prescribed to the 50% isodose line, for a median treated volume of 5.6 cc. Four patients (7%) suffered from local recurrence. Local recurrence-free, intracranial recurrence-free and overall survival at 1 year were 97.5%, 57.6% and 62.4% respectively. In total, 23 patients (41%) suffered from intracranial recurrence outside the tumor bed. In univariate analysis concomitant GK treatment of multiple lesions and the tumor bed was associated with a decrease in ICMFS (HR 1.16 1.005-1.34 p 0.04). In multivariate analysis a non-lung primary tumor was significantly associated with a decrease in ICMFS (HR 8.04 1.82-35.4 p 0.006). An increase in performance status (PS) and in the initial number of cerebral metastases significantly reduced overall survival (HR 5.4 1.11-26.3 p 0.037, HR 2.7 1.004-7.36 p 0.049, respectively) and One radiation necrosis histologically proven. Our study confirmed that postoperative GK after resection of cerebral metastases is an efficient and well-tolerated technique, to treat volumes of all sizes (0.8 to 40 cc). Iterative SRS or salvage WBRT can be performed in cases of intracranial relapse, postponing WBRT with its potential side effects.

Complex chest wall reconstruction after excision of malignant phyllodes tumour.

Phyllodes tumour is a rare breast tumour which is locally invasive, and full thickness chest wall involvement by phyllodes is rarely reported. A woman presented with recurrent phyllodes tumour and multilobulated exophytic mass of size 18.5×5.3 cm in anterior chest wall which was abutting the right 2nd-7th rib, left 3rd-5th rib and costal cartilages. She underwent wide excision of the left chest wall tumour with excision of left 3rd-5th rib, with polypropylene mesh and pedicled lattismus dorsi myocutaneous flap reconstruction. After recovery, 3 weeks later, she underwent wide excision of the phyllodes tumour on the right chest wall with excision of 2nd-7th rib, lateral border of sternum, right crus of the diaphragm and the lower lobe of the right lung. Anterior chest wall was reconstructed using scaffold made from Steinmann pins and polypropylene mesh with greater omentum pedicled flap and split thickness skin graft.

A multifunctional non-viral vector for the delivery of MTH1-targeted CRISPRCas9 system for non-small cell lung cancer therapy.

Clustered regularly interspaced short palindromic repeats (CRISPR)CRISPR-associated protein 9 (Cas9) system adapted from bacteria is a programmable nuclease-based genome editing tool. The long-lasting effect of gene silencing or correction is beneficial in cancer treatment. Considering the need to broaden the practical application of this technology, highly efficient non-viral vectors are urgently required. We prepared a multifunctional non-viral vector that could actively target tumor cells and deliver CRISPRCas9 plasmids into nuclei of cancer cells. Protamine sulfate (PS) which contains nuclear localization sequence was utilized to condense plasmid DNA and facilitate nuclei-targeted delivery. Liposome-coated proteinDNA complex avoided the degradation of nuclease in blood circulation. The obtained PSLippCas9 was further modified with distearoyl phosphoethanolamine-polyethylene glycol-hyaluronic acid (HA) to endow the vector ability to actively target tumor cell. Results suggested that PSHA-Lip could deliver CRISPRCas9 plasmids into nuclei of tumor cells and induce genome editing effect. With the disruption of MTH1 (mutT homolog1) gene, the growth of non-small cell lung cancer was inhibited. Moreover, cell apoptosis in tumor tissue was promoted, and liver metastasis of non-small cell lung cancer (NSCLC) was reduced. Our study has provided a therapeutic strategy targeting MTH1 gene for NSCLC therapy. STATEMENT OF SIGNIFICANCE CRISPRCas9 as a powerful tool for genome editing has drawn much attention. The long-lasting effect possesses unique advantage in cancer treatment. Non-viral vectors have high loading capacity, high safety and low immunogenicity, playing an important role in CRISPRCas9 delivery. In our study, a multifunctional non-viral vector for the efficient delivery of CRISPRCas9 plasmid was constructed. With the active targeting ligand and nuclei-targeting component, the cargo was efficiently delivered into cell nuclei and exerted genome editing effect. By using this vector, we successfully inhibited the growth and induced the apoptosis of non-small cell lung cancer by disrupting MTH1 expression with good safety. Our work provided an efficient non-vial vector for CRISPRCas9 delivery and explored the possibility for cancer treatment.

Small-cell lung cancer brain metastasis From molecular mechanisms to diagnosis and treatment.

Lung cancer is the most malignant human cancer worldwide, also with the highest incidence rate. However, small-cell lung cancer (SCLC) accounts for 14 % of all lung cancer cases. Approximately 10 % of patients with SCLC have brain metastasis at the time of diagnosis, which is the leading cause of death of patients with SCLC worldwide. The median overall survival is only 4.9 months, and a long-tern cure exists for patients with SCLC brain metastasis due to limited common therapeutic options. Recent studies have enhanced our understanding of the molecular mechanisms leading to meningeal metastasis, and multimodality treatments have brought new hopes for a better cure for the disease. This review aimed to offer an insight into the cellular processes of different metastatic stages of SCLC revealed by the established animal models, and into the major diagnostic methods of SCLC. Additionally, it provided in-depth information on the recent advances in SCLC treatments, and highlighted several new models and biomarkers with promises to improve the prognosis of SCLC.

Traditional Chinese Medicine has great potential as candidate drugs for lung cancer A review.

With high mortality and morbidity rates, lung cancer (LC) has become one of the major threats to human health. The treatment strategies for LC currently face issues, such as drug resistance and body tolerance. Traditional Chinese medicine (TCM) is characterized by novel pharmacological mechanisms, low toxicity, and limited side effects. TCM includes a substantial number of biologically active ingredients, several of which are effective monomeric agents against LC. An increasing number of researchers are focusing their efforts on the discovery of active anti-cancer ingredients in TCM. In this review, we summarized the anti-LC mechanisms of five types of TCM monomeric compounds. Our goal is to provide research ideas for the identification of new prospective medication candidates for the treatment of LC. We collected reports on the anti-LC effects of TCM monomers from web databases, including PubMed, Science Direct, Web of Science, and Europe PubMed Central. Among the keywords used were lung cancer, traditional Chinese medicine, pharmacology, and their combinations thereof. Then, we systematically summarized the anti-LC efficacy and related mechanisms of TCM monomers. Based on the available literature, this paper reviewed the therapeutic effects and mechanisms of five types of TCM monomers on LC. The characteristics of TCM monomers include the capabilities to suppress the tumor cell cycle, inhibit proliferation, induce apoptosis, promote autophagy, inhibit tumor cell invasion and metastasis, and enhance efficacy or reduce drug resistance when combined with cytotoxic agents and other methods to arrest the progression of LC and prolong the survival of patients. TCM contains numerous flavonoids, alkaloids, terpenoids, polyphenols, and other active compounds that are effective against LC. Given their chemical structure and pharmacological properties, these monomers are suitable as candidate drugs for the treatment of LC.

Effect of acetone fraction of Ottelia alismoides on the G2M cell cycle arrest and apoptosis in the human carcinoma cell lines.

The North-eastern parts of India have immense therapeutic floras, Ottelia alismoides is an aquatic plant that has been in use for a long time in traditional medicine for treating diseases like cancer, tuberculosis, diabetes, febrifuge, hemorrhoids, and rubefacient. In lung and skin carcinoma cells with a high rate of proliferation and metastasis including drug resistance and non-specific target activity, generates important challenges towards their treatment strategy. Thus, finding novel therapeutic targets to treat lung and skin cancer progression is essential to enhance the patients survival with treatment. The purpose of this study was to evaluate the apoptotic potential of acetone extract of O. alismoides (L.) Pers. (OA-AC) and to identify the compounds responsible for this effect, HRLC-MS-QTOF analysis of the extract has been undertaken along with in-silico molecular docking analysis of the identified compounds. A549 and A431 cells were treated with acetone extract of O. alismoides (OA-AC) at 24 h and 48 h exposure and cell cycle phase distribution was evaluated and also apoptosis induction activity was evaluated by OA-EtBr staining and Mitochondrial outer membrane potential assay. Western blotting was performed for the evaluation of apoptotic protein expression. At last, the HR-LCMS of OA-AC was analyzed to identify the compounds responsible for the apoptotic activity of the extract. The cell cycle phase distribution analysis in A549 and A431 cells at 24hrs exposure with 10 μgmL and 25 μgmL of OA-AC showed a potent arrest or blockage at the G2M phase of the cell cycle with reduced expression of cyclin B and p-Cdc2. At 48 h exposure, apoptosis was observed in these cancer cells with elevated expression of Bax, p21 and cleaved caspase 3 and reduced expression of the Bcl2. AO-EtBr staining of these cancer cells reveals that the death induced by OA-AC was apoptotic in nature with depolarization of mitochondrial membrane due to loss or damage of the mitochondrial membrane. The HRLC-MS-QTOF analysis of OA-AC depicted 14 major isolable compounds and molecular docking analysis displayed 4 compounds that might act as an inhibitor of cyclin B for G2M phase arrest that leads to apoptotic induction in the cells.

Factors Associated With Smoking Cessation Attempts in Lung Cancer Screening A Secondary Analysis of the National Lung Screening Trial.

Lung cancer remains the leading cause of cancer-related mortality in the United States. The National Lung Screening Trial (NLST) demonstrated a 20% reduction in lung cancer mortality resulting from lung cancer screening (LCS) with an additive reduction from smoking abstinence. However, successful smoking cessation within LCS is variable. What patient and treatment factors are associated with attempts to quit smoking among those screened for lung cancer In a secondary analysis of the American College of Radiology Imaging Network arm of the NLST, patient demographics, patient smoking behaviors, and tobacco treatment variables were stratified by patient smoking status. The Cox proportional hazards ratio was used to evaluate each variables effect on attempting to quit smoking. Seven thousand three hundred sixty-nine patients were smoking actively at enrollment in the NLST. Of the patients who reported they were smoking, 73.4% did not receive any pharmacologic tobacco treatment. More patients who attempted to quit received pharmacologic tobacco treatment than those who continued to smoke (nicotine replacement therapy NRT, 18.0% vs 12.4% P < .01 bupropion, 7.9% vs 6.9% P .02 both NRT and bupropion, 5.6% vs 3.9% P < .01). Stable users were more likely to be women (47.8% vs 43.8% P < .01), to be African American (8.2% vs 6.3% P .007), to be unmarried (43.2% vs 36.9% P < .01), and to have less than a college education (47.7% vs 42.3% P < .01). Patients with high dependence who received dual therapy with bupropion and NRT showed the highest likelihood of quit attempt (hazard ratio, 2.07 95% CI, 1.75-2.44). In this analysis, only one-quarter of patients who underwent LCS and who smoked were treated with pharmacologic therapy, which is associated with increased likelihood of attempting to quit. Certain characteristics are associated with difficulty with attempting to quit smoking. Those with high nicotine dependence benefitted most from dual pharmacologic therapy.

Steroidal saponin components and their cancer cell cytotoxicity from Paris rugosa.

The chemical components and availability of Paris rugosa were investigated for the first time, using a UPLC-MSMS-based molecular networking strategy and phytochemical research. Ultimately, eleven undescribed steroidal saponins, parisrugosides A-K, and ten known analogs were identified. Their structures were confirmed using comprehensive spectroscopic data and chemical methods. The aglycones of parisrugosides A-D are first spirostanes with an epoxy group at C-5C-6, a hydroxy group at C-7, and a double bond at C-8C-9 or C-8C-14. Parisrugosides G and H possess an undescribed spirostane aglycone with two double bonds located at C-5C-6 and C-8C-9, which are conjugated with a carbonyl group at C-7. The isolates were evaluated for their cytotoxicity against five human cancer cell lines (human HL-60 leukemia, A549 lung, MCF-7 breast, SMMC-7721 liver, and SW480 colon solid cancer cell lines). Parisyunnanoside D, kingianoside K, and dichotomin displayed significant cytotoxicity against these cancer lines, with IC

Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations.

KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regulator of the unfolded protein response (UPR). Following up on our recent discoveries that GRP78 haploinsufficiency suppresses both KRAS

Real-world observational study of current treatment patterns and outcomes in recurrent or locally advancedmetastatic non-small cell lung cancer.

Treatment for recurrent or advancedmetastatic non-small cell lung cancer (aNSCLC) has advanced in the past 5 years with immunotherapy (IO). This study sought to describe first-line (1L) aNSCLC treatment patterns and clinical outcomes. In this retrospective, multisite cohort study, community oncologists reported data for randomly selected stage IIIBIV, EGFR-ALK wild-type aNSCLC patients who initiated 1L systemic therapy from 01012016 to 12312019. Follow-up was through November 2020. Demographics, clinical characteristics, treatment patterns, disease response, progression, and deathlast follow-up date were described. Overall response rate (ORR) was calculated using tumor measurements applying RECIST v1.1 guidelines. Progression-free survival (PFS) and overall survival (OS) were calculated from 1L initiation by Kaplan-Meier method. 497 patients from 46 sites were included. The most common 1L regimens (%) were platinum-doublet chemotherapy plus IO (PDCIO) (40.6%), PDC (29.4%), IO monotherapy (20.7%), and PDCbevacizumab (6.2%). From 2016 to 2019, 1L PDC declined from 63% to 10%, whereas 1L PDCIO increased from 14% to 58%. The ORRs were 64.9%, 32.9%, 60.2%, and 61.3% for 1L PDCIO, PDC, IO monotherapy, and PDCbevacizumab, respectively. Median 1L PFSOS (months) was 15.626.5, 5.313.7, 17.8not reached, 10.818.6, respectively, for PDCIO, PDC, IO monotherapy, and PDCbevacizumab. Among patients who received only 1L treatment (n 299), 41.5% had no further therapy and were deceased. Although the 1L treatment paradigm has recently shifted to IO-based regimens, 41.5% did not survive past 1L. Median 1L PFS did not exceed 1.5 years and median OS remained limited across all 1L treatment groups, illustrating continued unmet aNSCLC therapeutic needs.

Identification of ALK-positive patients with advanced NSCLC and real-world clinical experience with crizotinib in Spain (IDEALK study).

To determine the incidence of ALK translocations in patients with advancedmetastatic NSCLC in Spain, to describe the clinical characteristics of these patients, and to evaluate the effectiveness and safety of treatment with crizotinib in a real-world setting. This is an observational prospective and retrospective cohort study to determine the incidence of ALK translocations and to analyze the effectiveness and safety of crizotinib in a real-world setting. Patient characteristics, treatment patterns, time to best overall response, duration of treatment, objective response rates (ORR), rates of adverse events (AE), progression free survival (PFS) and overall survival (OS) were evaluated in the ALK study cohort of patients treated with crizotinib (prospective and retrospective). ALK incidence and quality of life (QoL) questionnaires were measured from patients included in the prospective cohort. The incidence of ALK translocations was 5.5 % (31 of 559 patients). Compared with ALK-negative patients, ALK-positive patients were significantly younger, predominantly female, and non-smokers. In the crizotinib effectiveness and safety study, 91 patients (42 prospective, 49 retrospective) with ALK-positive NSCLC (43.9 % in first-line, 56.1 % in second or more lines) were included. The ORR was 59.3 % and the median duration of response was 13.5 months (IQR, 5.3-26.2). The median PFS was 15.8 months (95 % CI, 11.8-22.3) and the median OS was 46.5 months, with 53 patients (58.2 %) still alive at data cut-off date. Frequently reported AEs included elevated transaminases, gastrointestinal disorders, and asthenia. Most patients (76.5 %) reported improved or stable scores for global QoL during treatment. The observed incidence of ALK translocations in NSCLC patients is aligned with published reports. This analysis of the real-world clinical experience in Spain confirms the therapeutic benefit and safety of crizotinib in advancedmetastatic ALK-positive NSCLC. gov NCT02679170.

Integrating microarray-based spatial transcriptomics and single-cell RNA-sequencing reveals tissue architecture in esophageal squamous cell carcinoma.

The tumor microenvironment (TME) serves as an important factor in tumorigenesis and metastasis. Although distinct cell subsets can be identified via single-cell RNA sequencing (scRNA-seq), the spatial composition of cells within the TME is difficult to characterise. Tissue samples were collected from three patients with esophageal squamous cell carcinoma (ESCC), and scRNA-seq was performed to identify distinct cell subsets. In addition, a microarray-based spatial transcriptomics (ST) method was used to characterise the spatial landscape of expression data via an array of spots. Using multimodal intersection analysis (MIA) to integrate scRNA-seq and ST, the exact cellular components of the tumor and stromal regions were annotated. The subpopulations of seven stromal cells were identified within the TME of ESCC, and the architecture of scRNA-seq-determined subsets was mapped in cancer and stromal regions. The distribution of various stromal cells and their subpopulations was heterogeneous. Compared with immune cells, non-immune stromal cells were significantly enriched in the TME. Most subsets of epithelial cells were enriched in the cancer regions, whereas inflammatory cancer-associated fibroblasts were correlated with the stromal regions. Furthermore, TME features were different between metastatic and non-metastatic samples and between the primary and metastatic sites of the metastatic sample. This study revealed the spatial landscape of various cell subsets within the TME and the potential cross-talk among diverse cells, which provides novel insights into cancer intervention. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Discrepancies Between the Cost of Advanced Lung Cancer Treatment and How Much Is Reimbursed by the Brazilian Public Healthcare System.

Lung cancer is the leading cause of cancer-related death worldwide, and most patients are diagnosed of advanced disease. Molecular-targeted therapy and immunotherapy increase survival among these patients. In this study, we compared the cost of the best treatments available with the amount reimbursed by the Brazilian public healthcare system (Sistema Único de Saúde SUS) to treat advanced lung cancer. The authors divided lung cancer into 10 subtypes according to histology and molecular profile. A panel of experts defined the best treatment sequencing for each subtype. The authors considered only drug costs retrieved from the Brazilian Health Regulatory Agency official data. The progression-free survival of each regimen was considered as treatment duration. The cost estimate included all postprogression therapies weighted by each subtype proportional frequency. The amount reimbursed by SUS was the sum of the monthly budget accumulated during the estimated treatment duration and then for the proportional frequency of each subtype. The budget reimbursed by SUS for treating each advanced lung cancer case in Brazil is R$8000.00 in average whereas the cost estimate for the best treatment available is R$729 454.00 per case, which represents a difference of 9118%. The budget impact to ensure the reimbursement needed to acquire the best treatments available was estimated in near R$13 billion annually. The cost estimate of the best treatment available for advanced lung cancer in Brazil is much higher than the amount reimbursed by SUS. This budgetary gap leads to a major access barrier that may compromise the survival outcomes of SUS users.

Evaluation of Harms Reporting in U.S. Cancer Screening Guidelines.

Cancer screening should be recommended only when the balance between benefits and harms is favorable. This review evaluated how U.S. cancer screening guidelines reported harms, within and across organ-specific processes to screen for cancer. To describe current reporting practices and identify opportunities for improvement. Review of guidelines. United States. Patients eligible for screening for breast, cervical, colorectal, lung, or prostate cancer according to U.S. guidelines. Information was abstracted on reporting of patient-level harms associated with screening, diagnostic follow-up, and treatment. The authors classified harms reporting as not mentioned, conceptual, qualitative, or quantitative and noted whether literature was cited when harms were described. Frequency of harms reporting was summarized by organ type. Harms reporting was inconsistent across organ types and at each step of the cancer screening process. Guidelines did not report all harms for any specific organ type or for any category of harm across organ types. The most complete harms reporting was for prostate cancer screening guidelines and the least complete for colorectal cancer screening guidelines. Conceptualization of harms and use of quantitative evidence also differed by organ type. This review considers only patient-level harms. The authors did not verify accuracy of harms information presented in the guidelines. The review identified opportunities for improving conceptualization, assessment, and reporting of screening process-related harms in guidelines. Future work should consider nuances associated with each organ-specific process to screen for cancer, including which harms are most salient and where evidence gaps exist, and explicitly explore how to optimally weigh available evidence in determining net screening benefit. Improved harms reporting could aid informed decision making, ultimately improving cancer screening delivery. National Cancer Institute.

Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.

This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P 0.035) and disease-free survival (P 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P 0.043 and P 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS.

Artificial Intelligence-Powered Prediction of

Several studies reported the possibility of predicting genetic abnormalities in non-small-cell lung cancer by deep learning (DL). However, there are no data of predicting We selected 66 The maximum area under the curve was 0.73 (50% threshold 95% CI, 0.65 to 0.82) in the resolution of 1.0 μmpix. In this resolution, with an The

The Portfolio Diet and Incident Type 2 Diabetes Findings From the Womens Health Initiative Prospective Cohort Study.

A plant-based dietary pattern, the Portfolio Diet, has been shown to lower LDL cholesterol and other cardiovascular disease risk factors. However, no study has evaluated the association of this diet with incident type 2 diabetes. This analysis included 145,299 postmenopausal women free of diabetes at baseline in the Womens Health Initiative (WHI) Clinical Trials and Observational Study from 1993 to 2021. Adherence to the diet was assessed with a score based on six components (high in plant protein soy and pulses, nuts, viscous fiber, plant sterols, and monounsaturated fat and low in saturated fat and cholesterol) determined from a validated food-frequency questionnaire. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association of the Portfolio Diet, alongside the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets, with incident type 2 diabetes, with adjustment for potential confounders. Over a mean follow-up of 16.0 years, 13,943 cases of incident type 2 diabetes were identified. In comparisons of the highest with the lowest quintiles of adherence, the HRs for risk of incident type 2 diabetes were 0.77 (95% CI 0.72, 0.82) for the Portfolio Diet, 0.69 (0.64, 0.73) for the DASH diet, and 0.78 (0.74, 0.83) for the Mediterranean diet. These findings were attenuated by 10% after additional adjustment for BMI. Greater adherence to the plant-predominant Portfolio, DASH, and Mediterranean diets was prospectively associated with lower risk of type 2 diabetes in postmenopausal women.

Low-Dose Extrapolation Factors Implied by Mortality and Incidence Data from the Japanese Atomic Bomb Survivor Life Span Study Data.

Assessment of the effect of low dose and low-dose-rate exposure depends critically on extrapolation from groups exposed at high dose and high-dose rates such as the Japanese atomic bomb survivor data, and has often been achieved via application of a dose and dose-rate effectiveness factor (DDREF). An important component of DDREF is the factor determining the effect of extrapolation of dose, the so-called low-dose extrapolation factor (LDEF). To assess LDEF models linear (or linear quadratic) in dose are often fitted. In this report LDEF is assessed via fitting relative rate models that are linear or linear quadratic in dose to the latest Japanese atomic bomb survivor data on solid cancer, leukemia and circulatory disease mortality (followed from 1950 through 2003) and to data on solid cancer, lung cancer and urinary tract cancer incidence. The uncertainties in LDEF are assessed using parametric bootstrap techniques. Analysis is restricted to survivors with <3 Gy dose. There is modest evidence for upward curvature in dose response in the mortality data. For leukemia and for all solid cancer excluding lung, stomach and breast cancer there is significant curvature (P < 0.05). There is no evidence of curvature for circulatory disease (P > 0.5). The estimate of LDEF for all solid cancer mortality is 1.273 95% confidence intervals (CI) 0.913, 2.182, for all solid cancer mortality excluding lung cancer, stomach cancer and breast cancer is 2.183 (95% CI 1.090, >100) and for leukemia mortality is 11.447 (95% CI 2.390, >100). For stomach cancer mortality LDEF is modestly raised, 1.077 (95% CI 0.526, >100), while for lung cancer, female breast cancer and circulatory disease mortality the LDEF does not much exceed 1. LDEF for solid cancer incidence is 1.186 (95% CI 0.942, 1.626) and for urinary tract cancer is 1.298 (95% CI <0, 7.723), although for lung cancer LDEF is not elevated, 0.842 (95% CI 0.344, >100).

Predicting survival in metastatic non-small cell lung cancer patients with poor ECOG-PS A single-arm prospective study.

Patients with advanced non-small cell lung cancer (NSCLC) are a heterogeneous population with short lifespan. We aimed to develop methods to better differentiate patients whose survival was >90 days. We evaluated 83 characteristics of 106 treatment-naïve, stage IV NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) >1. Automated machine learning was used to select a model and optimize hyperparameters. 100-fold bootstrapping was performed for dimensionality reduction for a second (lite) model. Performance was measured by C-statistic and accuracy metrics in an out-of-sample validation cohort. The lite model was validated on a second independent, prospective cohort (N 42). Network analysis (NA) was performed to evaluate the differences in centrality and connectivity of features. The selected method was ExtraTrees Classifier, with C-statistic of 0.82 (p < 0.01) and accuracy of 0.81 (p 0.01). The lite model had 16 variables and obtained C-statistic of 0.84 (p < 0.01) and accuracy of 0.75 (p 0.039) in the first cohort, and C-statistic of 0.706 (p < 0.01) and accuracy of 0.714 (p < 0.01) in the second cohort. The networks of patients with lower survival were more interconnected. Features related to cachexia, inflammation, and quality of life had statistically different prestige scores in NA. Machine learning can assist in the prognostic evaluation of advanced NSCLC. The model generated with a reduced number of features showed high accessibility and reasonable metrics. Features related to quality of life, cachexia, and performance status had increased correlation and importance scores, suggesting that they play a role at later disease stages, in line with the biological rationale already described.

Identification of nine mutant genes and establishment of three prediction models of organ tropism metastases of non-small cell lung cancer.

Most Non-small cell lung cancer (NSCLC) patients tend to have metastases at the initial diagnosis. However, limited knowledge has been established regarding which factors, are associated with its metastases. This study aims to identify more biomarkers associated with its organ tropism metastasis and to establish models for prediction of its metastatic organs. We performed targeted next-generation sequencing (NGS) to detect genes related to lung cancer in 272 patients with primary advanced NSCLC from Northeast China. We adopted Fisher test, multivariate logistic regression analysis to identify metastasis-related gene mutations and to establish prediction models. Mutations of EGFR (p 0.0003, OR 2.554) (especially EGFR L858R p 0.02, OR 2.009), ATM (p 0.008, OR 11.032), and JAK2 (p 0.009, OR Inf) were positively and of TP53 exon4mut (p 0.001, OR 0.173) was negatively correlated with lung metastasis, and those of CSF1R (p 0.01, OR Inf), KIT (p 0.03, OR 4.746), MYC (p 0.05, OR 7.938), and ERBB2 (p 0.02, OR 2.666) were positively correlated with pleural dissemination those of TP53 (p 0.01, OR 0.417) was negatively, while of SMAD4 (p 0.03, OR 4.957) was positively correlated with brain metastasis of NSCLC. Additionally, smoking history (p 0.004, OR 0.004) was negatively correlated with pleural dissemination of NSCLC. Furthermore, models for prediction of lung metastasis (AUC 0.706), pleural dissemination (AUC 0.651), and brane metastasis (AUC 0.629) were established. Taken together, this study revealed nine mutant genes and smoking history associated with organ tropism metastases of NSCLC and provided three models for the prediction of metastatic organs. This study enables us to predict the organs to which non-small cell lung cancer metastasizes before it does develop.

Identification of a dysregulated ceRNA network modulated by copy number variation-driven lncRNAs in lung squamous cell carcinoma.

Lung cancer is primarily responsive for cancer death, and its progression is aggressively affected by copy number variation (CNV). Through bioinformatics approach, a ceRNA network of CNV-driven lncRNAs in lung squamous cell carcinoma (LUSC) patients was constructed. Data on normal and LUSC tumor tissue from The Cancer Genome Atlas (TCGA)-LUSC dataset were subjected to differential analysis, and differentially expressed lncRNAs (DElncRNAs), DEmiRNAs, and DEmRNAs were obtained. Based on TCGA-LUSC, CNVs of normal and tumor tissue samples were then compared using a Chi-square test, and lncRNAs were intersected based on their CNVs and expression alternation. In combination with the Kruskal-Wallis test, CNV-driven lncRNAs were acquired. Afterwards, miRNAs and mRNAs that interacted with CNV-driven lncRNAs were obtained based on databases (LncBase, starBase, miRDB, mirDIP and TargetScan), DElncRNAs, DEmiRNAs and DEmRNAs, and correlation analysis. The acquired lncRNAs, miRNAs and mRNAs were subjected to Cytoscape software to construct a CNV-driven ceRNA network, which involved 5 lncRNAs (MIR143HG, LINC00702, MIR22HG, RP11-180 N14.1, RP11-473 M20.9), 6 miRNAs (miR-3200-3p, miR-1301-3p, miR-93-3p, miR-96-5p, miR-96-5p, miR-130b-5p, miR-205-5p) and 80 mRNAs. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses indicated that downstream mRNAs were mainly correlated with blood vessel development and T cell-mediated immunity. In summary, we devoted to analyzing CNV-related lncRNAs, mRNAs, and miRNAs in LUSC, thus clarifying 5 lncRNAs that may influence the malignant progression of LUSC. The ceRNA network regulated by these lncRNAs may be the novel pathogenesis of LUSC.

Lentiviral vector transduction provides nonspecific immunogenicity for syngeneic tumor models.

Lentivirus-based transduction systems are widely used in biological science and cancer biology, including cancer immunotherapy. However, in in vivo transplanted tumor model, the immunogenicity of these transduced cells was not appropriately addressed. Here, we used empty vector-transduced mouse melanoma (B16) and carcinoma (lewis lung carcinoma) cells transplanted tumor model to study the immune response due to the transduction processes. We showed that the overall in vivo tumor growth rate gets reduced in transduced cells only in immune-competent mice but not in nude mice. This data indicate the involvement of the immune system in the in vivo tumor growth restriction in the transduced group. Further studies showed that specific activation of CD8

Sex-specific associations between susceptibility to Mycobacterium avium complex-lung disease and PDCD-1 gene polymorphisms.

Mycobacterium avium complex-lung disease (MAC-LD) preferentially occurs in postmenopausal women and may have immune exhaustion involving the programmed cell death-1 (PD-1) pathway. Whether sex-specific associations between susceptibility to MAC-LD and PDCD-1 gene polymorphisms exist remains unknown. MAC-LD patients (n 152) and controls (n 167) were included at two medical centers in Taiwan. Five single nucleotide polymorphisms in PDCD-1 genes were genotyped and their associations with MAC-LD and soluble PD-1 (sPD-1) protein analyzed, especially in sex subgroups. PDCD-1 rs2227982 polymorphism was additively associated with increased risk of MAC-LD in females (AA vs AG vs GG, adjusted odds ratio aOR) 2.205 95% CI 1.108-4.389, p 0.024) and the rs10204525 TT genotype was associated with low risk in males (TT vs TC and CC, aOR 0.396 0.176-0.890, p 0.025). Notably, compared with males with rs10204525 TT, females with rs2227982 AG and with AA had 2.7- and 5.0-fold increased risks, respectively. Overall, sPD-1 levels were lower in the female subgroup with rs2227982 AG and AA than in the remainder (median 46.7 interquartile range 33.7-71.5 pgml vs 66.2 48.6-101.5 pgml, p < 0.001). PDCD-1 genetic polymorphisms were associated with the risk of MAC-LD in a sex-specific pattern, possibly through regulation of PD-1 expression.

Oncologic outcomes of segmentectomy for stage IA radiological solid-predominant lung cancer >2 cm in maximum tumour size.

We aimed to compare the outcomes of segmentectomy with those of lobectomy in clinical-stage IA radiological solid-predominant non-small-cell lung cancer (NSCLC) >2 cm in maximum tumour size. A retrospective review was performed for radiological solid-predominant NSCLC >2-3 cm in maximum tumour size with a ground-glass opacity component on thin-section computed tomography. Multivariable or propensity score-matched analyses were performed to control for confounders for survival. Overall survival (OS) was analysed using a Kaplan-Meier estimation. Of the 215 eligible cases, segmentectomy and lobectomy were performed in 46 and 169 patients. Multivariable analysis revealed that standardized uptake value (hazard ratio 1.148, 95% confidence interval 1.032-1.276, P 0.011) was an independently significant prognosticators of OS, while the operative mode was not associated (hazard ratio 0.635, 95% confidence interval 0.132-3.049, P 0.570). The 5 y-OS was excellent and did not differ significantly between segmentectomy and lobectomy (95.5% vs 90.2% P 0.697), which was also shown in the propensity score analysis (96.8% vs 94.0% P 0.406), with a median follow-up time of 5.2 years. Locoregional recurrence was found in 2 (4.3%) segmentectomy and 13 (7.7%) lobectomy (P 0.443). In the subgroup analysis stratified by solid component size, the 5 y-OS was similar between segmentectomy and lobectomy in the c-T1b and c-T1c groups, respectively c-T1b (n 163) 94.1% vs 91.8% P 0.887 and c-T1c (n 52) 100% vs 84.9% P 0.197. Segmentectomy showed similar oncological results compared to lobectomy in solid-predominant NSCLC with a ground-glass opacity component >2-3 cm in maximum tumour size. More prospective randomized trials are needed to adequately expand the indication of anatomic segmentectomy for early-stage NSCLC.

Cryobiopsy for pneumonitis diagnosis in NSCLC immunotherapy.

Nowadays immunotherapy is considered the tip of the arrow as treatment for non-small cell lung cancer for inoperable patients. Programmed death-ligand 1 is considered a valuable marker for the success of immunotherapy. The higher the score ≥50% the more successful the treatment will be. However previous studies have presented favorable data even for those patients where the programmed death-ligand 1 was ≤50% or even 0%, therefore it can be administered as first line treatment in these patients with the addition of chemotherapy or radiotherapy. Other treatment modalities are tested as surrogates like gene therapy with immunotherapy to improve the results in patients with programmed death-ligand 1 was ≤50% or even 0%. The main issue for these patients is an adverse effect pneumonitis, in case we will present the valuable method of lung parenchyma sampling with cryobiopsy for early diagnosis of immunotherapy induced pneumonitis.

HuR affects chemoresistance of small cell lung cancer by regulating FGFRL1 expression.

Human antigen R (HuR), an RNA-binding protein, has been demonstrated to serve an oncogenic role in various types of cancer. Fibroblast growth factor receptor-like 1 (FGFRL1) has been shown to regulate small cell lung cancer (SCLC) chemoresistance. In the present study, the role of HuR in chemoresistance of SCLC, as well as its possible molecular mechanism involving FGFRL1, was explored by reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8 assay, flow cytometry and RNA immunoprecipitation. The results revealed that HuR expression levels were markedly upregulated in drug-resistant SCLC cell lines (H69AR and H446DDP) compared with in the parental cell lines (H69 and H446). Knockdown of HuR in drug-resistant SCLC cells enhanced drug sensitivity, cell apoptosis and cell cycle arrest. Furthermore, molecular mechanism studies indicated that HuR could bind and regulate FGFRL1 expression levels to increase FGFRL1 mRNA stability. Taken together, the present study suggested that HuR may mediate chemoresistance of SCLC by regulating FGFRL1 expression. HuR may represent a prognostic predictor and a potential target for overcoming chemoresistance in SCLC.

Retracted MicroRNA‑19a‑3p inhibits the cellular proliferation and invasion of non‑small cell lung cancer by downregulating UBAP2L.

This retracts the article DOI 10.3892etm.2020.8926..

Crosstalk between gut microbiota and COVID-19 impacts pancreatic cancer progression.

Pancreatic cancer (PC) is one of the most common causes of cancer-associated death worldwide, with a low rate of 5-year survival. Currently, the pathogenesis of PC is complicated, with no efficient therapy. Coronavirus disease 2019 (COVID-19) disease caused by severe acute respiratory syndrome coronavirus 2 further exacerbates the challenge of patients with PC. The alteration of gut microbiota caused by COVID-19 infection may impact PC progression in patients

Bilateral Orbital Inflammation as a Manifestation of Paraneoplastic Syndrome.

Paraneoplastic neurologic syndromes (PNS) constitute a rare group of disorders whose optimal treatment is yet to be established. We report a patient with bilateral orbital inflammation associated with PNS, who responded well to surgical resection of the primary tumor. An 83-year-old woman was referred to our department for treatment of a progressive reduction in visual acuity and palpebral swelling in both eyes for the past 2 months. She was scheduled to undergo thoracic surgery for lung cancer. The best-corrected visual acuity (BCVA) in the right and left eye had worsened from 0.3 to 0.5 one month before she was referred to our department to 0.03 and 0.07, respectively. A slit-lamp examination revealed edema in both eyelids. Goldmann perimetry revealed several paracentral scotomas with constriction of the peripheral visual fields of both eyes, along with central absolute scotomas in V-4e isopter in the right eye. Magnetic resonance imaging revealed swelling of the bilateral extraocular muscles, which compressed the bilateral optic nerves at the orbital apex. Seven days after the resection of the lung cancer, the BCVA improved to 0.07 and 0.15 in the right and left eyes, respectively, without concomitant immunotherapy. Intravenous methylprednisolone (500 mgday) was administered for 3 days to treat the residual orbital inflammation. Fourteen days after surgery, the BCVA further improved to 0.4 and 0.5 in the right and left eyes, respectively. Swelling of the bilateral extraocular muscles and the visual field abnormalities improved dramatically. Early diagnosis is crucial for the management of PNS.

Case Report Durable response to immuno-chemotherapy in a case of ROS1 fusion-positive advanced lung adenocarcinoma A case report.

Immune checkpoint inhibitors (ICIs) have greatly transformed the treatment and improved the prognosis for patients with non-small cell lung cancer (NSCLC) without driver gene alterations. However, the effects of ICI combination therapy in ROS1 fusion-positive NSCLC remains unclear. Herein, we present a case with ROS1 fusion-positive NSCLC treated with ICI plus chemotherapy. The patient achieved a continuous partial response (PR) to ICI plus chemotherapy and a more than 35 months progression free survival. This case demonstrates that ICI plus chemotherapy is a promising option for patients with ROS1 fusion-positive NSCLC.

Fucoxanthin prevents breast cancer metastasis by interrupting circulating tumor cells adhesion and transendothelial migration.

Metastasis is the leading cause of cancer-related death and a critical challenge in improving cancer treatment today. Circulating tumor cells (CTCs) adhesion to and across the vascular endothelium are critical steps in the establishment of micrometastatic foci away from the primary tumor. Therefore, we believe that interrupting CTCs adhesion to endothelium and transendothelial migration may efficiently prevent cancer metastasis. Fucoxanthin (Fx) is an algal carotenoid widely distributed in brown algae, macroalgae, and diatoms. Previous studies have found that Fx has various pharmacological activities, including antidiabetic, antioxidant, anti-inflammatory, anti-obesity, antimalarial, anticancer, and so on. However, it remains unclear whether Fx has a preventive effect on cancer metastasis. Here, we found that Fx interrupts breast cancer cells MCF-7 adhesion to endothelium and transendothelial migration, thus inhibiting CTCs-based pulmonary metastasis

An acetonic extract and secondary metabolites from the endolichenic fungus

Corrigendum Docetaxel-loaded novel nano-platform for synergistic therapy of non-small cell lung cancer.

This corrects the article DOI 10.3389fphar.2022.832725..

Treatment of Stage I Lung Cancer Detected by Computed Tomography Screening.

Reducing lung cancer deaths through early detection by computed tomography (CT) screening requires delivery of effective treatment. We performed this retrospective study to determine the types of treatment used for screen-detected stage I lung cancer at our academic center and to compare the demographic and clinical characteristics of patients by type of treatment. All persons screened in the lung cancer screening program at our institution through June 16, 2021, were included. Those with screening CT findings needing follow-up were managed through a thoracic surgery clinic. Demographic and clinical characteristics of patients diagnosed with having stage I lung cancer through June 16, 2021, were compared by type of treatment, with follow-up through December 31, 2021. Stage I NSCLC was diagnosed in 54 of 2203 persons screened (2.5%), on the basis of biopsy in 37 and on imaging findings in 17 patients in whom a tissue diagnosis could not be obtained. Treatment was by lobectomy in 18, sublobar resection in 14, and stereotactic body radiation therapy (SBRT) in 22. Patients treated with SBRT had lower forced expiratory volume in 1 second ( Many patients with screen-detected stage I lung cancer are medically unfit for lobectomy, and a variety of treatments are being used. Assessment of treatment-based outcomes will be critical for ensuring an optimal balance of the risks and benefits of CT screening in a medically diverse population.

Randomized double-blind clinical study in patients with COVID-19 to evaluate the safety and efficacy of a phytomedicine (P2Et).

It has been proposed that polyphenols can be used in the development of new therapies against COVID-19, given their ability to interfere with the adsorption and entrance processes of the virus, thus disrupting viral replication. Seeds from In this work, a phase II multicenter randomized double-blind clinical trial on COVID-19 patients was designed to evaluate the impact of the P2Et treatment on the clinical outcome and the immunological parameters related to the evolution of the disease. The Trial was registered with the number No. NCT04410510 Patients treated with P2Et were discharged on average after 7.4 days of admission vs. 9.6 days in the placebo group. Although a decrease in proinflammatory cytokines such as G-CSF, IL-15, IL-12, IL-6, IP10, MCP-1, MCP-2 and IL-18 was observed in both groups, P2Et decreased to a greater extent G-CSF, IL-6 and IL-18 among others, which are related to lower recovery of patients in the long term. The frequency of T lymphocytes (LT) CD3, LT double negative (CD3CD4-CD8-), NK cells increased in the P2Et group where the population of eosinophils was also significantly reduced. In the murine bleomycin model, P2Et also reduced lung inflammation and fibrosis. P2Et was able to reduce the viral replication of murine and human coronaviruses Taken together these results suggest that P2Et could be consider as a good co-adjuvant in the treatment of COVID-19. httpsclinicaltrials.govct2showNCT04410510, identifier NCT04410510.

FOXP family DNA methylation correlates with immune infiltration and prognostic value in NSCLC.

Circulating vascular endothelial growth factor and cancer risk A bidirectional mendelian randomization.

In observational studies, circulating vascular endothelial growth factor (VEGF) has been reported to be associated with certain types of cancer. The purpose of this study was to verify whether there is a causal relationship between circulating VEGF and different types of cancer and the direction of the causal relationship. Summary statistical data were obtained from the corresponding genome-wide association studies (GWASs) to investigate the causal relationship between circulating VEGF and the risk of several cancers, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, anus and anal canal cancer, prostate cancer, esophageal cancer, kidney cancer, bladder cancer, thyroid cancer, malignant neoplasm of the brain and malignant neoplasm of the liver and intrahepatic bile ducts. A two-sample bidirectional Mendelian randomization (MR) analysis and sensitivity tests were used to evaluate the validity of causality. A causal relationship was detected between circulating VEGF and colorectal cancer (OR 1.21, 95% CI 1.11-1.32,

Necroptosis-related lncRNA in lung adenocarcinoma A comprehensive analysis based on a prognosis model and a competing endogenous RNA network.

Comprehensive analysis to identify GNG7 as a prognostic biomarker in lung adenocarcinoma correlating with immune infiltrates.

Case report A persistently expanded T cell response in an exceptional responder to radiation and atezolizumab for metastatic non-small cell lung cancer.

Most patients with advanced non-small cell lung cancer (NSCLC) do not achieve a durable remission after treatment with immune checkpoint inhibitors. Here we report the clinical history of an exceptional responder to radiation and anti-program death-ligand 1 (PD-L1) monoclonal antibody, atezolizumab, for metastatic NSCLC who remains in a complete remission more than 8 years after treatment. Sequencing of the patients T cell repertoire from a metastatic lesion and the blood before and after anti-PD-L1 treatment revealed oligoclonal T cell expansion. Characterization of the dominant T cell clone, which comprised 10% of all clones and increased 10-fold in the blood post-treatment, revealed an activated CD8

Characteristics of the immune microenvironment and their clinical significance in non-small cell lung cancer patients with ALK-rearranged mutation.

Although immune checkpoint inhibitors (ICIs) are one of the most important treatments for advanced-stage non-small-cell lung cancer (NSCLC), NSCLC patients with ALK-rearranged usually dont obtain a clinical benefit. The reason may be related to the unique tumor microenvironment (TME). We evaluated the characteristics of immune biomarkers of the TME and their prognostic value in ALK-rearranged NSCLC. Tumor samples from patients with ALK-rearranged (N 39) and EGFR- (N 40)KRAS- (N 30) mutated NSCLC were collected. Immunohistochemistry (IHC) was used to assess the expression of 9 tumor immune markers as well as 6 immune markers of tumor-infiltrating cells. To research the TME of ALK-rearranged NSCLC, EGFRKRAS-positive patients were used as controls. Furthermore, the correlation between the efficacy and prognosis of patients with advanced-stage (IIIC-IV) ALK rearrangements treated with targeted drugs was analyzed in terms of the TME. The proportion of PD-L1 tumors was lower in ALK-positive NSCLC than in KRAS-positive NSCLC. Besides, the proportion of T cells expressing TIM-3-CD8 (15.38%), CTLA4-CD8 (12.82%), LAG3-CD8 (33.33%) and PD-1-CD8 (2.56%) in ALK-positive NSCLC was lower than that in EGFRKRAS-positive NSCLC. The expression of CD3, CD8 T cells and CD20 B cells was lower in ALK-positive NSCLC than in KRAS-positive NSCLC (p < 0.0001, < 0.005, and < 0.001, respectively). Nevertheless, the level of CD4 helper T cells was higher in ALK-positive NSCLC than in EGFRKRAS-positive NSCLC (p < 0.0001 and p < 0.05, respectively). The repression of TIM3 was higher in ALK-positive NSCLC than in KRAS-positive NSCLC (p < 0.001). In addition, our data showed that high expression of PD-L1 (HR 0.177, 95% CI 0.038-0.852, p 0.027) and CTLA4 (HR 0.196, 95% CI 0.041-0.947, p 0.043) was related to lower OS in advanced-stage ALK- rearranged NSCLC patients treated with ALK tyrosine kinase inhibitors (TKIs). Immunosuppressive status was characteristic of the TME in patients with ALK-positive NSCLC compared with EGFRKRAS-positive NSCLC. High expression of PD-L1 and CTLA4 was an adverse prognostic factor in advanced-stage ALK-rearranged NSCLC patients treated with ALK-TKIs. Immunotherapy for ALK-rearranged patients requires further exploration and validation by clinical trials.

The efficacy of immune checkpoint inhibitors in advanced

The efficacy of immune checkpoint inhibitors (ICIs) in pretreated We collected 116 consecutive NSCLC patients with sensitive The ORR in patients with target lesions was 31.25% (95% CI 22.18-41.52), and the DCR in all patients was 65.66% (95% CI 55.44-74.91). The overall median PFS was 5.0 months (95% CI 3.0-6.6), and the median OS was 15.9 months (95% CI 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI 3.0-13.3) and a median OS of 29.0 months (95% CI 11.7-NE). Primary Our study suggests that ICI-based combination therapy is a potential strategy for